Quinoline derivatives

ABSTRACT

Quinoline derivatives are useful as neuropeptide Y (NPY) receptor ligands and are particularly effective as neuropeptide Y (NPY) antagonists. These compounds are useful in pharmaceutical preparations for the treatment or prevention of arthritis, cardiovascular diseases, diabetes, renal failure, eating disorders, or obesity.

BACKGROUND OF THE INVENTION

[0001] The present invention is concerned with novel quinolinederivatives useful as neuropeptide Y (NPY) receptor ligands,particularly neuropeptide Y (NPY) antagonists.

SUMMARY OF THE INVENTION

[0002] The subject invention provides compounds of formula:

[0003] wherein:

[0004] R¹ is hydrogen, alkyl, alkoxyalkyl, alkenyl, alkinyl,hydroxyalkyl, aralkyl, heterocyclylalkyl, cycloalkylalkyl, NH₂—SO₂—,monoalkylamino-SO₂—, dialkylamino-SO₂—, alkyl-SO₂—, aryl, NH₂-alkyl,monoalkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylalkyl,carboxyalkyl, aryl-SO₂—O-alkyl, cycloalkyl, or cycloalkylalkyl;

[0005] R² is hydrogen, halogen, alkyl, alkenyl, alkinyl, aralkyl,heteroarylalkyl, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl,aryloxy, arylamino, heteroarylamino, NH₂—, monoalkylamino, dialkylamino,heterocyclyl, arylalkylamino, heteroarylalkylamino, aryl, arylalkoxy, orheteroarylalkoxy;

[0006] R³ is hydrogen, alkyl, NH₂—, monoalkylamino, dialkylamino, oralkoxy;

[0007] R⁴ is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, NH₂—,monoalkylamino, dialkylamino, acetylamino, cyano, hydroxyalkyl,alkoxyalkyl, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclyl,heterocyclyloxy, heterocyclyloxyalkoxy, hydroxyalkoxy, alkoxycarbonyl,carboxy, heterocyclylalkyl, alkyl-SO₂—, or aryl-SO₂—;

[0008] R⁵ is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, NH₂—,monoalkylamino, dialkylamino, acetylamino, cyano, hydroxyalkyl,alkoxyalkyl, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclyl,heterocyclyloxy, heterocyclyloxyalkoxy, hydroxyalkoxy, alkoxycarbonyl,carboxy, heterocyclylalkyl, alkyl-SO₂—, or aryl-SO₂—;

[0009] A is a 5- to 10-membered mono- or bicyclic saturated heterocyclicring comprising the nitrogen atom which is attached to the quinolinering or a 5- to 10-membered mono- or bicyclic saturated heterocyclicring comprising the nitrogen atom which is attached to the quinolinering, which is substituted by one or two further heteroatoms which areindependently selected from the group consisting or oxygen, sulfur andnitrogen;

[0010] and pharmaceutically acceptable salts or esters thereof.

[0011] A preferred embodiment is where R¹ is hydrogen, alkyl,alkoxyalkyl, alkenyl, alkinyl, hydroxyalkyl, aralkyl, heterocyclylalkyl,cycloalkylalkyl, NH₂—SO₂—, monoalkylamino-SO₂—, dialkylamino-SO₂—, oralkyl-SO₂—; R⁴ is hydrogen, alkyl, alkoxy, hydroxy, NH₂—,monoalkylamino, dialkylamino, acetylamino, or cyano; R⁵ is hydrogen; andA is a saturated ring consisting of the nitrogen atom which is attachedto the quinoline ring and a —(CH₂)_(n)— moiety with n being 4, 5, or 6.Preferred compounds are where R¹ is hydrogen, cycloalkylalkyl, aralkyl,or heteroarylalkyl. Further preferred compounds are where R¹ ishydrogen, aralkyl or heteroarylalkyl, favorably hydrogen, phenylalkyl,pyridinylalkyl, phenylalkyl wherein the phenyl cycle is substituted byone to three substituents independently selected from the groupconsisting of alkoxy, cyano and halogen, and pyridinylalkyl wherein thepyridinyl cycle is substituted by one to three substituentsindependently selected from the group consisting of alkoxy, cyano andhalogen. Especially preferred is where R¹ is hydrogen,cyclopropylmethyl, (methoxyphenyl) methyl, (cyanophenyl) methyl,(chlorophenyl) methyl, pyridinylmethyl, chloropyridinylmethyl, orfluoropyridinylmethyl.

[0012] Favored groups of compounds are where R² is hydrogen, alkyl orhalogen. Especially preferred is where R² is hydrogen, butyl, fluoro,chloro or bromo.

[0013] R³ is favorably hydrogen, alkyl, or NH₂—. Methyl is a preferredalkyl group.

[0014] R⁴ is favorably hydrogen, alkoxy, alkoxyalkyl, hydroxyalkyl orhydroxy. A is preferably a pyrrolidinyl or azepanyl ring, with thepyrrolidinyl ring being favored.

[0015] The subject invention also provides compounds of formula:

[0016] wherein:

[0017] R^(1′) is hydrogen, phenylalkyl, pyridinylalkyl, phenylalkylwherein the phenyl cycle is substituted by a substituent selected fromthe group consisting of alkoxy, cyano and halogen, and pyridinylalkylwherein the pyridinyl cycle is substituted by a substituent selectedfrom the group consisting of alkoxy, cyano and halogen;

[0018] R^(2′) is is hydrogen, alkyl or halogen;

[0019] R^(3′) is hydrogen or alkyl;

[0020] A′ is selected from the group consisting of pyrrolidinyl,pyrrolidinyl substituted by hydroxy, alkyloxy, hydroxyalkyl oralkyloxyalkyl, and azepanyl;

[0021] and pharmaceutically acceptable salts and esters thereof.

[0022] Some favored compounds are where R^(3′) is hydrogen or methyl, A′is pyrrolidinyl, R^(2′) is alkyl, such as butyl, and R^(1′) is hydrogen,e.g. 6-butyl-4-pyrrolidin-1-yl-quinolin-7-ol or a pharmaceuticallyacceptable salt or ester thereof R^(1′) may also be (cyanophenyl)methyl,e.g. 4-(6-butyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrileor a pharmaceutically acceptable salt or ester thereof

[0023] Other favored compounds are where R^(3′) is methyl, A′ isazepanyl, R^(2′) is hydrogen, and R^(1′) is pyridinylmethyl, e.g.4-azepan-1-yl-2-methyl-7-(pyridin-4-ylmethoxy)-quinoline or apharmaceutically acceptable salt or ester thereof. R^(1′)may also be(cyanophenyl)methy, e.g.4-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile or3-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile or apharmaceutically acceptable salts or esters thereof.

[0024] Preferred compounds include those where A′ is pyrrolidinyl orpyrrolidinyl which is substituted by hydroxy, alkyloxy, hydroxyalkyl oralkyloxyalkyl. A favored group is where A′ is pyrrolidinyl, R^(2′) ishydrogen or halogen. R^(1′) can favorably-be hydrogen, phenylalkylwherein the phenyl cycle is substituted by a substituent selected fromthe group consisting of alkoxy, cyano and halogen, and pyridinylalkylwherein the pyridinyl cycle is substituted by a substituent selectedfrom the group consisting of alkoxy, cyano and halogen. When R^(1′) 0 ishydrogen, 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol or a pharmaceuticallyacceptable salt or ester thereof is favored. When R^(1′) is(methoxyphenyl)methyl,7-(3-methoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline andpharmaceutically acceptable salts and esters thereof is favored. WhenR^(1′) is (cyanophenyl)methyl,2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl) -benzonitrile and4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile, aswell as pharmaceutically acceptable salts and esters thereof arefavored. Where R^(1′) is (chlorophenyl)methyl,7-(3-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline and7-(4-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline, as well aspharmaceutically acceptable salts and esters thereof are preferred.R^(1′) is (chloropyridinyl)methyl,7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinolineand pharmaceutically acceptable salts and esters thereof are favored.When R^(2′) is halogen, such as fluoro, and R^(1′) is(cyanophenyl)methyl, the comopund4-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)benzonitrileand pharmaceutically acceptable salts and esters thereof are preferred.Likewise, when R^(1′) is (fluoropyridinyl)methyl,6-fluoro-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinolineand pharmaceutically acceptable salts and esters thereof are preferredand when R′ is (chloropyridinyl)methyl,7-(2-chloro-pyridin-3-ylmethoxy)-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolineand pharmaceutically acceptable salts and esters thereof are preferred.

[0025] Preferred compounds also include those where A′ is pyrrolidinylwhich is substituted by hydroxy, alkyloxy, hydroxyalkyl oralkyloxyalkyl. When A′ is pyrrolidinyl which is substituted by hydroxy,R^(1′) is (cyanophenyl)methyl, and R^(2′) is hydrogen, the compounds (S)and(R)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileand pharmaceutically acceptable salts and esters thereof are favored.When A′ is pyrrolidinyl which is substituted by alkyloxy, such asmethoxy, and R^(1′) is (cyanophenyl)methyl, the compound(S)-4-[4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileand pharmaceutically acceptable salts and esters thereof are preferred.If A′ is pyrrolidinyl which is substituted by ethoxy, R^(2′) ishydrogen, and R^(1′) is (cyanophenyl)methyl, then(S)-4-[4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileor a pharmaceutically acceptable salt or ester thereof is favored. IfR^(1′) is (fluoropyridinyl)methyl, then (S)4-(3-ethoxy-pyrrolidin-1-yl)-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-quinolineor a pharmaceutically acceptable salt or ester thereof is favored. IfR^(1′) is (chloropyridinyl)methyl, then (S)7-(2-chloro-pyridin-3-ylmethoxy)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolineor a pharmaceutically acceptable salt or ester thereof is favored.

[0026] When A′ is pyrrolidinyl which is substituted by hydroxyalkyl,e.g. hydroxymethyl, R^(2′) is hydrogen, and R^(1′) is(fluoropyridinyl)methyl, then(S)-{1-[7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-quinolin-4-yl]-pyrrolidin-2-yl}-methanolor a pharmaceutically acceptable salt or ester thereof is the favoredcompound. If R^(1′) is (chloropyridinyl)methyl, then the preferredcompound is(S)-{1-[7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-quinolin-4-yl]-pyrrolidin-2-yl}-methanolor a pharmaceutically acceptable salt or ester thereof, and if R^(1′) is(cyanophenyl)methy, then the preferred compound is (S) or(R)-4-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileor a pharmaceutically acceptable salt or ester thereof.

[0027] Other favored compounds are where R²′ is halogen, e.g. fluoro,and R^(1′) is (cyanophenyl)methyl, for example(S)-4-[6-fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileor a pharmaceutically acceptable salt or ester thereof. If A′ ispyrrolidinyl which is substituted by alkyloxyalkyl, such asmethoxymethyl, and R^(2′) is hydrogen, and R^(1′) is(fluoropyridinyl)methyl, then the favored compound is(S)-7-(2-fluoro-pyridin-3-ylmethoxy)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolineor a pharmaceutically acceptable salt or ester thereof. Should R^(1′) be(chloropyridinyl)methyl, then(S)-7-(2-chloro-pyridin-3-ylmethoxy)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolineor a pharmaceutically acceptable salt or ester thereof would be thefavored compound.

[0028] For brevity, each and every combination of substituents has notbeen listed individually. However, it is intended that each and everycombination of substituents be considered described and enabled by thepresent specification.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The subject invention will be described in terms of its preferredembodiments that are set forth to aid in understanding the invention.While illustrative of the invention, these embodiments are not to beconstrued as limiting.

[0030] The invention is concerned especially with compounds of formula I

[0031] and pharmaceutically acceptable salts and esters thereof, wherein

[0032] R¹ is hydrogen, alkyl, alkoxyalkyl, alkenyl, alkinyl,hydroxyalkyl, aralkyl, heterocyclylalkyl, cycloalkylalkyl, NH₂—SO₂—,monoalkylamino-SO₂—, dialkylamino-SO₂—, alkyl-SO₂—, aryl, NH₂-alkyl,monoalkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylalkyl,carboxyalkyl, aryl-SO₂—O-alkyl, cycloalkyl or cycloalkylalkyl;

[0033] R² is hydrogen, halogen, alkyl, alkenyl, alkinyl, aralkyl,heteroarylalkyl, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl,aryloxy, arylamino, heteroarylamino, NH₂—, monoalkylamino, dialkylamino,heterocyclyl, arylalkylamino, heteroarylalkylamino, aryl, arylalkoxy orheteroarylalkoxy;

[0034] R³ is hydrogen, alkyl, NH₂—, monoalkylamino, dialkylamino oralkoxy;

[0035] R⁴ is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, NH₂—,monoalkylamino, dialkylamino, acetylamino, cyano, hydroxyalkyl,alkoxyalkyl, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclyl,heterocyclyloxy, heterocyclyloxyalkoxy, hydroxyalkoxy, alkoxycarbonyl,carboxy, heterocyclylalkyl, alkyl-SO₂— or aryl-SO₂—;

[0036] R⁵ is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, NH₂—,monoalkylamino, dialkylamino, acetylamino, cyano, hydroxyalkyl,alkoxyalkyl, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclyl,heterocyclyloxy, heterocyclyloxyalkoxy, hydroxyalkoxy, alkoxycarbonyl,carboxy, heterocyclylalkyl, alkyl-SO₂— or aryl-SO₂—; and

[0037] A is a 5- to 10-membered mono- or bicyclic saturated heterocyclicring comprising the nitrogen atom which is attached to the quinolinering and optionally one or two further heteroatoms which areindependently selected from oxygen, sulfur and nitrogen.

[0038] The compounds of formula I and their pharmaceutically usablesalts and are novel and have valuable pharmacological properties. Theyare neuropeptide ligands, for example neuropeptide receptor antagonistsand in particular, they are selective neuropeptides Y Y5 receptorantagonists.

[0039] Neuropetide Y is a 36 amino acid peptide that is widelydistributed in the central and peripheral nervous systems. This peptidemediates a number of physiological effects through its various receptorsubtypes. Studies in animals have shown that neuropeptide Y is apowerful stimulus of food intake, and it has been demonstrated thatactivation of neuropeptide Y Y5 receptors results in hyperphagia anddecreased thermogenesis. Therefore compounds that antagonise neuropetideY at the Y5 receptor subtype represent an approach to the treatment ofeating disorders such as obesity and hyperphagia.

[0040] The current approach is aiming at medical intervention to induceweight loss or prevention of weight gain. This is achieved byinterfering with appetite control, which is mediated by theHypothalamus, an important brain region proven to control food intake.Herein, neuropeptide Y (NPY) has been proven to be one of the strongestcentral mediators of food intake in several animal species. IncreasedNPY levels result in profound food intake. Various receptors ofneuropeptide Y (NPY) have been described to play a role in appetitecontrol and weight gain. Interference with these receptors is likely toreduce appetite and consequently weight gain. Reduction and long-termmaintenance of body weight can also have beneficial consequences on conassociated risk factors such as arthritis, cardiovascular diseases,diabetes and renal failure.

[0041] Accordingly, the compounds of formula I can be used in theprophylaxis or treatment of of arthritis, cardiovascular diseases,diabetes, renal failure and particularly eating disorders and obesity.

[0042] The subject invention provides compounds of formula I and theirsalts and esters, the use of such compounds as therapeutically activesubstances, a process for the manufacture of such compounds,intermediates, pharmaceutical compositions, medicaments containing suchcompounds, and their pharmaceutically usable salts and esters. The useof the compounds, esters and salts for the prophylaxis and/or therapy ofillnesses, especially in the treatment or prophylaxis of arthritis,cardiovascular diseases, diabetes, renal failure and particularly eatingdisorders such as hyperphagia and particularly obesity, is alsoprovided. In addition the invention includes the use of the compounds,salts and esters for the production of medicaments for the treatment orprophylaxis of arthritis, cardiovascular diseases, diabetes, renalfailure and particularly eating disorders and obesity.

[0043] In the present description the term “alkyl”, alone or incombination, signifies a straight-chain or branched-chain alkyl groupwith 1 to 8 carbon atoms, preferably a straight or branched-chain alkylgroup with 1 to 6 carbon atoms and particularly preferred a straight orbranched-chain alkyl group with 1 to 4 carbon atoms Examples ofstraight-chain and branched C₁-C₈ alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls,the isomeric hexyls, the isomeric heptyls and the isomeric octyls,preferably methyl and ethyl and most preferred methyl.

[0044] The term “cycloalkyl”, alone or in combination, signifies acycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkylring with 3 to 6 carbon atoms. Examples of C₃-C₈ cycloalkyl arecyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl,methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl,methyl-cyclohexyl, dimethyl-cyclohexyl, cycloheptyl and cyclooctyl,preferably cyclopropyl.

[0045] The term “alkoxy”, alone or in combination, signifies a group ofthe formula alkyl-O— in which the term “alkyl” has the previously givensignificance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec.butoxy and tert.butoxy, 2-hydroxyethoxy,2-methoxyethoxypreferably methoxy and ethoxy and most preferred methoxy.

[0046] The term “aryloxy”, alone or in combination, signifies a group ofthe formula aryl-O— in which the term “aryl” has the previously givensignificance, such as phenyloxy.

[0047] The term “aryl”, alone or in combination, signifies a phenyl ornaphthyl group, preferably a phenyl group which optionally carries oneor more substituents each independently selected from halogen,trifluoromethyl, amino, alkyl, alkoxy, alkylcarbonyl, cyano, carbamoyl,alkoxycarbamoyl, methylendioxy, carboxy, alkoxycarbonyl, aminocarbonyl,alkyaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro and the like,such as phenyl, chlorophenyl, trifluoromethylphenyl, chlorofluorophenyl,aminophenyl, methylcarbonylphenyl, methoxyphenyl, methylendioxyphenyl,1-naphthyl and 2-naphthyl.

[0048] Preferred is phenyl, 3-chlorophenyl, 3-trifluoromethylphenyl,3-aminophenyl, 4-methylcarbonylphenyl, 4-methoxyphenyl and particularlyphenyl.

[0049] The term “aralkyl”, alone or in combination, signifies an alkylor cycloalkyl group as previously defined in which one hydrogen atom hasbeen replaced by an aryl group as previously defined. Preferred arebenzyl, benzyl substituted with hydroxy, alkoxy or halogen, preferablyfluorine. Particularly preferred is benzyl.

[0050] The term “heterocyclyl”, alone or in combination, signifies asaturated, partially unsaturated or aromatic 4- to 10-memberedheterocycle which contains one or more, preferably one ore two heteroatoms selected from nitrogen, oxygen and sulfur, wherein oxygen andparticularly nitrogen are preferred. If desired, it can be substitutedon one or more carbon atoms by halogen, alkyl, alkoxy, oxo, cyano,haloalkyl preferably trifluoromethyl and heterocyclyl, preferablymorpholinyl and pyrrolidinyl, and/or on a secondary nitrogen atom (i.e.—NH—) by alkyl, cycloalkyl, aralkoxycarbonyl, alkanoyl, phenyl orphenylalkyl or on a tertiary nitrogen atom (i.e. —N—) by oxido, withhalogen, alkyl, cycloalkyl and alkoxy being preferred. The term“heterocyclyl” also includes the term heteroaryl. Examples ofheterocyclyl groups are pyridinyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, 3,4-dihydro-1H-isoquinolinyl, azepanyl,tetrahydrofuranyl and thiophenyl, wherein each of these rings can besubstituted by one or more, preferably one or two substituentsindependently selected from alkyl, alkoxy, halogen, trifluoromethyl,cyano, morpholinyl and pyrrolidinyl. Particularly preferred examples ofheterocycly are pyridinyl, pyrrolidinyl, piperidinyl, morpholinyl,thiophenyl, tetrahydrofuranyl and furyl, wherein each of these rings isoptionally substituted with one or more, preferably one or twosubstituents selected from alkyl, alkoxy, halogen, trifluoromethyl,cyano, morpholinyl and pyrrolidinyl.

[0051] The term “heteroaryl”, alone or in combination, signifiesaromatic 5- to 10-membered heterocycle which contains one or more,preferably one or two hetero atoms selected from nitrogen, oxygen andsulfur, wherein nitrogen or oxygen are preferred. If desired, it can besubstituted on one or more carbon atoms by halogen, alkyl, alkoxy,cyano, haloalkyl, heterocyclyl, preferably trifluoromethyl. Preferredheteroaryl cycles are pyridinyl or thiophenyl optionaly substituted byone or more, preferably one or two substituents independently selectedfrom halogen, alkyl, alkoxy, cyano, haloalkyl, preferablytrifluoromethyl, and heterocyclyl, preferably morpholinyl orpyrrolidinyl.

[0052] The term “amino”, alone or in combination, signifies a primary,secondary or tertiary amino group bonded via the nitrogen atom, with thesecondary amino group carrying an alkyl or cycloalkyl substituent andthe tertiary amino group carrying two similar or different alkyl orcycloalkyl substituents or the two nitrogen substitutents togetherforming a ring, such as, for example, —NH₂, methylamino, ethylamino,dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl orpiperidino etc., preferably amino, dimethylamino and diethylamino andparticularly primary amino.

[0053] The term “halogen” signifies fluorine, chlorine, bromine oriodine and preferably fluorine, chlorine or bromine.

[0054] The term “alkenyl”, alone or in combination signifies astraight-chain or branched hydrocarbon residue comprising an olefinicbond and up to 8, preferably up to 6, particularly preferred up to 4carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl,2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl.

[0055] The term “alkinyl”, alone or in combination signifies astraight-chain or branched hydrocarbon residue comprising a carboncarbon triple bond and up to 8, preferably up to 6, particularlypreferred up to 4 carbon atoms. Examples of alkinyl groups are ethinyl,1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl and 3-butinyl.

[0056] The term “carboxy”, alone or in combination signifies the —COOHgroup.

[0057] The term “carboxyalkyl”, alone or in combination signifies analkyl group as defined before, wherein one or more, preferably onehydrogen atom is replaced by a carboxy group. An example iscarboxymethyl.

[0058] The term “hydroxyalkyl”, alone or in combination signifies analkyl group as define before, wherein one or more, preferably onehydrogen atom is replaced by a hydroxy group.

[0059] The term “aryloxy”, alone or in combination signifies the grouparyl-O—, wherein the term aryl is defined as before.

[0060] The term “cyano”, alone or in combination signifies the group—CN.

[0061] The term “heterocyclyloxy”, alone or in combination signifies thegroup heterocyclyl-O—, wherein the term heterocyclyl is defined asbefore.

[0062] The term “actetylamino”, alone or in combination signifies thegroup —NH—CO—CH₃.

[0063] The term “arylamino”, alone or in combination signifies the grouparyl-NH— or

[0064] wherein the term aryl is defined as before and, wherein both arylgroups are the same or are different.

[0065] The term “heteroarylamino”, alone or in combination signifies thegroup heteroaryl-NH— or

[0066] wherein the term heteroaryl is defined as before and, whereinboth heteroaryl groups are the same or are different.

[0067] The term “pharmaceutically acceptable salts” refers to thosesalts that retain the biological effectiveness and properties of thefree bases or free acids, which are not biologically or otherwiseundesirable. The salts are formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, preferably hydrochloric acid, and organicacids such as acetic acid, propionic acid, glycolic acid, pyruvic acid,oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, N-acetylcystein and the like. In addition these saltsmay be prepared form addition of an inorganic base or an organic base tothe free acid. Salts derived from an inorganic base include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium, magnesiumsalts and the like. Salts derived from organic bases include, but arenot limited to salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymineresins and the like. The compound of formula I can also be present inthe form of zwitterions. Particularly preferred pharmaceuticallyacceptable salts of compounds of formula I are the hydrochloride salts.

[0068] The compounds of formula I can also be solvated, e.g. hydrated.The solvation can be effected in the course of the manufacturing processor can take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration). The termpharmaceutically acceptable salts also includes physiologically usablesolvates.

[0069] “Pharmaceutically acceptable esters” means that compounds offormula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of thecompounds of formula (I), similar to the metabolically labile esters,which are capable of producing the parent compounds of formula (I) invivo, are within the scope of this invention.

[0070] The term “lipase inhibitor” refers to compounds which are capableof inhibiting the action of lipases, for example gastric and pancreaticlipases. For example orlistat and lipstatin as described in U.S. Pat.No. 4,598,089 are potent inhibitor of lipases. Lipstatin is a naturalproduct of microbial origin, and orlistat is the result of ahydrogenation of lipstatin. Other lipase inhibitors include a class ofcompound commonly referred to as panclicins. Panclicins are analogues oforlistat (Mutoh et al, 1994). The term “lipase inhibitor” refers also topolymer bound lipase inhibitors for example described in InternationalPatent Application WO99/34786 (Geltex Pharmaceuticals Inc.). Thesepolymers are characterized in that they have been substituted with oneor more groups that inhibit lipases. The term “lipase inhibitor” alsocomprises pharmaceutically acceptable salts of these compounds. The term“lipase inhibitor” preferably refers to orlistat.

[0071] Orlistat is a known compound useful for the control or preventionof obesity and hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul.1, 1986, which also discloses processes for making orlistat and U.S.Pat. No. 6,004,996, which discloses appropriate pharmaceuticalcompositions. Further suitable pharmaceutical compositions are describedfor example in International Patent Applications WO 00/09122 and WO00/09123.

[0072] Additional processes for the preparation of orlistat aredisclosed in European Patent Applications Publication Nos. 185,359,189,577, 443,449, and 524,495.

[0073] Orlistat is preferably orally administered from 60 to 720 mg perday in divided doses two to three times per day. Preferred is whereinfrom 180 to 360 mg, most preferably 360 mg per day of a lipase inhibitoris administered to a subject, preferably in divided doses two or,particularly, three times per day. The subject is preferably an obese oroverweight human, i.e. a human with a body mass index of 25 or greater.Generally, it is preferred that the lipase inhibitor be administeredwithin about one or two hours of ingestion of a meal containing fat.Generally, for administering a lipase inhibitor as defined above it ispreferred that treatment be administered to a human who has a strongfamily history of obesity and has obtained a body mass index of 25 orgreater.

[0074] Orlistat can be administered to humans in conventional oralcompositions, such as, tablets, coated tablets, hard and soft gelatincapsules, emulsions or suspensions. Examples of carriers which can beused for tablets, coated tablets, dragees and hard gelatin capsules arelactose, other sugars and sugar alcohols like sorbitol, mannitol,maltodextrin, or other fillers; surfactants like sodium lauryle sulfate,Brij 96, or Tween 80; disintegrants like sodium starch glycolate, maizestarch or derivatives thereof; polymers like povidone, crospovidone;talc; stearic acid or its salts and the like. Suitable carriers for softgelatin capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Moreover, the pharmaceuticalpreparations can contain preserving agents, solubilizers, stabilizingagents, wetting agents, emulsifying agents, sweetening agents, coloringagents, flavoring agents, salts for varying the osmotic pressure,buffers, coating agents and antioxidants. They can also contain stillother therapeutically valuable substances. The formulations mayconveniently be presented in unit dosage form and may be prepared by anymethods known in the pharmaceutical art. Preferably, orlistat isadministered according to the formulation shown in the Examples and inU.S. Pat. No. 6,004,996, respectively.

[0075] The compounds of formula I can contain several asymmetric centersand can be present in the form of optically pure enantiomers, mixturesof enantiomers such as, for example, racemates, optically purediastereioisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates.

[0076] In the nomenclature used in the present description the ringatoms of the quinoline ring are numbered as follows:

[0077] Preferred are compounds of the formula I, wherein

[0078] R¹ is hydrogen, alkyl, alkoxyalkyl, alkenyl, alkinyl,hydroxyalkyl, aralkyl, heterocyclylalkyl, cycloalkylalkyl, NH₂—SO₂—,monoalkylamino-SO₂—, dialkylamino-SO₂— or alkyl-SO₂—;

[0079] R² is hydrogen, halogen, alkyl, alkenyl, alkinyl, aralkyl,heteroarylalkyl, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl,aryloxy, arylamino, heteroarylamino, NH₂—, mono- or dialkylamino,heterocyclyl, arylalkylamino, heteroarylalkylamino, aryl, heteroaryl,arylalkoxy or heteroarylalkoxy;

[0080] R³ is hydrogen, alkyl, NH₂—, monoalkylamino, dialkylamino oralkoxy;

[0081] R⁴ is hydrogen, alkyl, alkoxy, hydroxy, NH₂—, monoalkylamino,dialkylamino, acetylamino or cyano;

[0082] R⁵ is hydrogen;

[0083] A is a saturated ring consisting of a nitrogen atom which isattched to the quinoline ring and a —(CH₂)_(n)— moiety with n being 4,5, or 6;

[0084] and pharmaceutically acceptable salts and esters thereof.

[0085] Preferred compounds of formula I are those, wherein R¹ ishydrogen, alkyl, alkenyl, hydroxyalkyl, aralkyl, heterocyclylalkyl,cycloalkylalkyl, dialkylamino-SO₂—, alkyl-SO₂—, dialkylaminoalkyl,alkoxycarbonylalkyl, aryl-SO₂—O-alkyl or cycloalkylalkyl.

[0086] In a further preferred embodiment of the invention R¹ ishydrogen, alkyl, alkoxyalkyl, alkenyl, alkinyl, hydroxyalkyl, aralkyl,heterocyclylalkyl, cycloalkylalkyl, NH₂—, mono- or dialkylamino-SO₂—, oralkyl-SO₂—. A further preferred embodiment of the present invention R¹is hydrogen, cycloalkylalkyl, aralkyl, or heteroarylalkyl. Furtherpreferred are compounds according to formula (I), wherein R¹ ishydrogen, aralkyl or heteroarylalkyl. Particularly preferred arecompounds of formula (I), wherein R¹ is hydrogen, phenylalkyl orpyridinylalkyl wherein the phenyl- and the pyridinyl cyles areoptionally substituted with one to three substituents independentlyselected from the group consisting of alkyl, alkoxy, cyano, or halogen,preferably, methyl, alkoxy, cyano, or halogen. Further particularlypreferred are compounds, wherein R¹ is hydrogen, cyclopropylmethyl,(methoxyphenyl)methyl, (cyanophenyl)methyl, (chlorophenyl)methyl,pyridinylmethyl, (fluropyridinyl)methyl, (chloropyridinyl)methyl, or(methylpyridinyl)methyl. Very preferred are compounds, wherein R¹ ishydrogen, cyclopropylmethyl, (methoxyphenyl)methyl, (cyanophenyl)methyl,(chlorophenyl)methyl or pyridinylmethyl. Particularly preferred arecompounds of formula I, wherein R¹ is hydrogen, cyclopropylmethyl,(methoxyphenyl)methyl, (cyanophenyl)methyl, (chlorophenyl)methyl,pyridinylmethyl, chloropyridinylmethyl or fluoropyridinylmethyl.

[0087] In a preferred emodiment of the present invention R² is hydrogen,halogen, alkyl, alkenyl, alkinyl, aralkyl, heteroarylalkyl,hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl, aryloxy,arylamino, heteroarylamino, NH₂—, mono- or dialkylamino oraryl(alkyl)amino. In another preferred embodiment of the invention R² ishydrogen, alkyl, or halogen. Particularly preferred are compounds offormula (I), wherein R² is hydrogen. Likewise preferred are compoundsaccording to formula (I), wherein R² is alkyl. Other preferred compoundsof formula (I) are those, wherein R² is hydrogen, butyl, fluoro, chloroor bromo. Particularly preferred are hydrogen, butyl, fluoro or bromo.

[0088] A preferred aspect of the present invention are compoundsaccording to formula I, wherein R³ is hydrogen, alkyl, aralkoxy,heteroarylalkoxy, NH₂—, mono- or di-alkylamino. Further preferredcompounds of formula (I) are those, wherein R³ is hydrogen, alkyl, orNH₂—. Preferred compounds are those, wherein R³ is alkyl, particularlymethyl.

[0089] Preferred are compounds of formula I, wherein R⁴ is hydrogen,alkyl, cycloalkyl, alkoxy, hydroxy, monoalkylamino, dialkylamino,hydroxyalkyl, alkoxyalkyl, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy,heterocyclyl, heterocyclyloxyalkoxy, hydroxyalkoxy, alkoxycarbonyl,heterocyclylalkyl or alkyl-SO₂—.

[0090] In a preferred embodiment of the invention R⁴ is hydrogen, alkylor alkoxy. Another preferred aspect of the present invention arecompounds of formula (I), wherein R⁴ is hydrogen or alkoxy. Particularlypreferred compounds of formula I are those, wherein R⁴ is hydrogen,alkoxy, alkoxyalkyl, hydroxyalkyl or hydroxy. Very preferred ishydrogen.

[0091] Further preferred are those compounds of formula I, wherein A isa 5- to 10-membered mono- or bicyclic saturated heterocyclic ringcomprising the nitrogen atom which is attached to the quinoline ring andoptionally one or two further oxygen atoms. Preferred compoundsaccording to formula I are those, wherein A is pyrrolidinyl, azepanyl,morpholinyl, 1,4-dioxa-8-aza-spiro(4.5)dec-8-yl or piperidinyl.

[0092] Other preferred compounds of formula (I) are those, wherein A isa pyrrolidinyl or azepanyl ring. Particularly preferred is apyrrolidinyl ring.

[0093] Preferred compounds of formula I are those, wherein R⁵ ishydrogen.

[0094] Examples of preferred compounds of formula (I) are

[0095] 1. 7-Benzyloxy-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0096] 2. 2-Methyl-4-pyrrolidin-1-yl-quinolin-7-ol;

[0097] 3. Dimethyl-sulfamic acid2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl ester;

[0098] 4. Methanesulfonic acid 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ylester;

[0099] 5. 7-Cyclopropylmethoxy-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0100] 6. 7-(3-Methoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0101] 7. 7-Methoxy-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0102] 8. 2-Methyl-7-(pyridin-2-ylmethoxy)-4-pyrrolidin-1-yl-quinoline;

[0103] 9. 7-Allyloxy-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0104] 10. 7-Isobutoxy-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0105] 11. 7-(2-Methoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0106] 12.2-Methyl-4-pyrrolidin-1-yl-7-(tetrahydro-furan-2-ylmethoxy)-quinoline;

[0107] 13. 7-(4-Methoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0108] 14. 2-(2-Methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0109] 15. 4-(2-Methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0110] 16. 2-Methyl-4-pyrrolidin-1-yl-7-(2-trifluoromethyl-benzyloxy)-quinoline;

[0111] 17.2-Methyl-4-pyrrolidin-1-yl-7-(3-trifluoromethyl-benzyloxy)-quinoline;

[0112] 18.2-Methyl-4-pyrrolidin-1-yl-7-(4-trifluoromethyl-benzyloxy)-quinoline;

[0113] 19. 7-(2-Chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0114] 20. 7-(3-Chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0115] 21. 7-(4-Chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0116] 22. 2-Methyl-7-(pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinoline;

[0117] 23. 3-(2-Methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0118] 24. 7-Isopropoxy-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0119] 25. 7-(2-Methoxy-ethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0120] 26.2-Methyl-7-(2-morpholin-4-yl-ethoxy)-4-pyrrolidin-1-yl-quinoline;

[0121] 27. 2-Methyl-7-(pyridin-4-ylmethoxy)-4-pyrrolidin-1-yl-quinoline;

[0122] 28.(S)-′7-Benzyloxy-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinoline;

[0123] 29. (S)-4-(3-Ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol;

[0124] 30.(S)-4-(3-Ethoxy-pyrrolidin-1-yl)-7-(3-methoxy-benzyloxy)-2-methyl-quinoline;

[0125] 31.(S)-4-[4-(3-Ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0126] 32.(S)-2-[4-(3-Ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0127] 33. 7-Benzyloxy-6-butyl-4-pyrrolidin-1-yl-quinoline;

[0128] 34. 6-Butyl-4-pyrrolidin-1-yl-quinolin-7-ol;

[0129] 35. 6-Butyl-7-methoxy-4-pyrrolidin-1-yl-quinoline;

[0130] 36. 6-Butyl-7-ethoxy-4-pyrrolidin-1-yl-quinoline;

[0131] 37. 6-Butyl-7-cyclopropylmethoxy-4-pyrrolidin-1-yl-quinoline;

[0132] 38. 4-(6-Butyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0133] 39. 4-Azepan-1-yl-7-benzyloxy-2-methyl-quinoline;

[0134] 40. 4-Azepan-1-yl-2-methyl-quinolin-7-ol;

[0135] 41. 4-Azepan-1-yl-2-methyl-7-(pyridin-4-ylmethoxy) -quinoline;

[0136] 42.4-(4-Azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile;

[0137] 43.3-(4-Azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile;

[0138] 44. 4-Azepan-1-yl-2-methyl-7-(pyridin-2-ylmethoxy)-quinoline;

[0139] 45. 6-Bromo-7-methoxy-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0140] 46. 6-Bromo-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol;

[0141] 47.4-(6-Bromo-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0142] 48. 7-Methoxy-4-pyrrolidin-1-yl-quinolin-2-ylamine;

[0143] 49. 7-Methoxy-4-pyrrolidin-1-yl-quinoline;

[0144] 50. 4-Pyrrolidin-1-yl-quinolin-7-ol;

[0145] 51.7-(3,5-dimethoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0146] 52.7-(3,4-dimethoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0147] 53. 7-ethoxy-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0148] 54.2-Methyl-7-(6-methyl-pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinoline;

[0149] 55.2-methyl-7-(2-methyl-pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinoline;

[0150] 56.7-(6-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0151] 57.7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0152] 58.7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0153] 59.7-(2-chloro-6-methyl-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0154] 60.7-(2-chloro-6-trifluoromethyl-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0155] 61.5-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-pyridine-2-carbonitrile;

[0156] 62.7-(5-chloro-thiophen-2-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0157] 63.2-methyl-4-pyrrolidin-1-yl-7-(thiophen-3-ylmethoxy)-quinoline;

[0158] 64. 4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-benzonitrile;

[0159] 65. (S)4-(3-ethoxy-pyrrolidin-1-yl)-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-quinoline;

[0160] 66. (S)7-(2-chloro-pyridin-3-ylmethoxy)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinoline;

[0161] 67. (S)4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-7-(pyridin-3-ylmethoxy)-quinoline;

[0162] 68. (S)5-[4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-pyridine-2-carbonitrile;

[0163] 69. 4-azepan-1-yl-7-(3-methoxy-benzyloxy)-2-methyl-quinoline;

[0164] 70. 2-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile;

[0165] 71. 4-azepan-1-yl-7-(3-chloro-benzyloxy)-2-methyl-quinoline;

[0166] 72. 4-Azepan-1-yl-7-(4-chloro-benzyloxy)-2-methyl-quinoline;

[0167] 73.2-methyl-7-(6-morpholin-4-yl-pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinoline;

[0168] 74.2-methyl-4-pyrrolidin-1-yl-7-(6-pyrrolidin-1-yl-pyridin-3-ylmethoxy)-quinoline;

[0169] 75.[2,2-dimethyl-3-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-propyl]-dimethyl-amine;

[0170] 76.2-methyl-7-(1-methyl-piperidin-4-yloxy)-4-pyrrolidin-1-yl-quinoline;

[0171] 77.2-methyl-4-pyrrolidin-1-yl-7-(tetrahydro-furan-3-yloxy)-quinoline;

[0172] 78.2-Methyl-7-(1-methyl-piperidin-4-ylmethoxy)-4-pyrrolidin-1-yl-quinoline;

[0173] 79.2-methyl-7-(3-morpholin-4-yl-propoxy)-4-pyrrolidin-1-yl-quinoline;

[0174] 80. (2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-acetic acidethyl ester;

[0175] 81. 2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-ethanol;

[0176] 82. oluene-4-sulfonic acid2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-ethyl ester;

[0177] 83.2-methyl-7-(3-pyridin-2-yl-propoxy)-4-pyrrolidin-1-yl-quinoline;

[0178] 84. 7-benzyloxy-2-methyl-4-morpholin-4-yl-quinoline;

[0179] 85. (S)-1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-3-ol;

[0180] 86. (R)-1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-3-ol;

[0181] 87.(S)-[1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-2-yl]-methanol;

[0182] 88.(S)-7-benzyloxy-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinoline;

[0183] 89.(S)-4-(2-Methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol;

[0184] 90.(S)-7-(2-chloro-pyridin-3-ylmethoxy)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinoline;

[0185] 91.(S)-7-(2-fluoro-pyridin-3-ylmethoxy)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinoline;

[0186] 92.(S)-7-cyclopropylmethoxy-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinoline;

[0187] 93.(S)-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol;

[0188] 94.(S)-{1-[7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-quinolin-4-yl]-pyrrolidin-2-yl}-methanol;

[0189] 95.(S)-{1-[7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-quinolin-4-yl]-pyrrolidin-2-yl}-methanol;

[0190] 96.(S)-2-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0191] 97.(S)-{1-[2-methyl-7-(pyridin-3-ylmethoxy)-quinolin-4-yl]-pyrrolidin-2-yl}-methanol;

[0192] 98.(S)-5-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-pyridine-2-carbonitrile;

[0193] 99. 7-benzyloxy-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0194] 100. 6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol;

[0195] 101.4-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0196] 102.6-fuoro-2-methyl-7-(pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinoline;

[0197] 103.6-fluoro-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0198] 104.7-(2-chloro-pyridin-3-ylmethoxy)-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0199] 105.6-fluoro-2-methyl-7-(2-methyl-pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinoline;

[0200] 106.3-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0201] 107.2-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0202] 108.7-cyclopropylmethoxy-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0203] 109.5-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-pyridine-2-carbonitrile;

[0204] 110.(R)-7-benzyloxy-4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinoline;

[0205] 111.(S)-7-benzyloxy-4-[3-(2-methoxy-ethoxy)-pyrrolidin-1-yl]-2-methyl-quinoline;

[0206] 112.(S)-7-benzyloxy-4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinoline;

[0207] 113.(S)-7-benzyloxy-4-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-2-methyl-quinoline;

[0208] 114.(S)-7-benzyloxy-4-[3-(3-methoxy-propoxy)-pyrrolidin-1-yl]-2-methyl-quinoline;

[0209] 115.7-benzyloxy-2-methyl-4-{(3S)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-pyrrolidin-1-yl}-quinoline;

[0210] 116.(S)-4-[3-(2-methoxy-ethoxy)-pyrrolidin-1-yl]-2-methyl-quinolin-7-ol;

[0211] 117. (S)-4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol;

[0212] 118.(S)-4-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol;

[0213] 119.(S)-4-[3-(3-methoxy-propoxy)-pyrrolidin-1-yl]-2-methyl-quinolin-7-ol;

[0214] 120.2-methyl-4-{(3S)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-pyrrolidin-1-yl}-quinolin-7-ol;

[0215] 121.(S)-4-{4-[3-(2-methoxy-ethoxy)-pyrrolidin-1-yl]-2-methyl-quinolin-7-yloxymethyl}-benzonitrile;

[0216] 122.(S)-4-[4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0217] 123.(S)-4-[4-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0218] 124.(S)-4-{4-[3-(3-methoxy-propoxy)-pyrrolidin-1-yl]-2-methyl-quinolin-7-yloxymethyl}-benzonitrile;

[0219] 125.(S)-4-{4-[3-(2-Hydroxy-ethoxy)-pyrrolidin-1-yl]-2-methyl-quinolin-7-yloxymethyl}-benzonitrile;

[0220] 126. (S)-[1-(7-benzyloxy-6-fluoro-2-methyl-quinolin-4-yl)-pyrrolidin-2-yl]-methanol;

[0221] 127.(S)-6-fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol;

[0222] 128.(S)-4-[6-fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0223] 129.(S)-5-[6-fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-pyridine-2-carbonitrile;

[0224] 130.(S)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0225] 131.(R)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0226] 132.(R,S)-4-[2-methyl-4-(2-methyl-pyrrolidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrile;

[0227] 133.(S)-4-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0228] 134.(R)-4-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0229] 135.(R)-4-[4-(3-dimethylamino-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0230] 136.(S)-4-[4-(3-dimethylamino-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0231] 137.(R)-4-[4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0232] 138.(S)-4-[4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0233] 139.(R,S)-4-[4-(2-isopropyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0234] 140.(S)-1-[7-(4-cyano-benzyloxy)-2-methyl-quinolin-4-yl]-pyrrolidine-2-carboxylicacid methyl ester;

[0235] 141.(R)-4-[2-methyl-4-(3-methylamino-pyrrolidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrile;

[0236] 142.(S)-4-[2-methyl-4-(3-methylamino-pyrrolidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrile;

[0237] 143.4-(2-methyl-4-piperidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0238] 144.4-(2-methyl-4-morpholin-4-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0239] 145.(R,S)-4-[4-(3-diethylamino-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0240] 146.(R,S)-4-[2-methyl-4-(3-pyridin-2-yl-pyrrolidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrile;

[0241] 147.(R,S)-4-[2-methyl-4-(3-pyridin-4-yl-pyrrolidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrile;

[0242] 148.(S)-4-[2-methyl-4-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrile;

[0243] 149.(R,S)-4-[4-(3-methanesulfonyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0244] 150.(R,S)-4-[2-methyl-4-(3-methyl-piperidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrile;

[0245] 151. 4-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile and

[0246] 152.(R,S)-4-[4-(3-hydroxymethyl-piperidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile.

[0247] Examples of particularly preferred compounds of formula (I) are

[0248] 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol;

[0249] 7-(3-methoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0250]2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0251]4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0252] 7-(3-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0253] 7-(4-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0254](S)-4-[4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0255] 6-butyl-4-pyrrolidin-1-yl-quinolin-7-ol;

[0256]4-(6-butyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0257] 4-azepan-1-yl-2-methyl-7-(pyridin-4-ylmethoxy)-quinoline;

[0258] 4-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile;

[0259] 3-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile;

[0260]7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0261] (S)4-(3-ethoxy-pyrrolidin-1-yl)-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-quinoline;

[0262] (S)7-(2-chloro-pyridin-3-ylmethoxy)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinoline;

[0263](S)-7-(2-chloro-pyridin-3-ylmethoxy)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinoline;

[0264](S)-7-(2-fluoro-pyridin-3-ylmethoxy)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinoline;

[0265](S)-{1-[7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-quinolin-4-yl]-pyrrolidin-2-yl}-methanol;

[0266](S)-{1-[7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-quinolin-4-yl]-pyrrolidin-2-yl}-methanol;

[0267]4-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile;

[0268]6-fluoro-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0269]7-(2-chloro-pyridin-3-ylmethoxy)-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinoline;

[0270](S)-4-[4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0271](S)-4-[6-fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0272](S)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0273](R)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile;

[0274](S)-4-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileand

[0275](R)-4-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile.

[0276] Processes for the manufacture of compounds of formula I are anobject of the invention.

[0277] The substituents and indices used in the following description ofthe processes have the significance given above unless indicated to thecontrary.

[0278] Compounds of formula I can be obtained according to scheme 1 fromcompounds of formula Ia comprising R² substituents according to theabove definition by an alkylation reaction with, e.g. K₂CO₃ as a baseand in a suited solvent such as DMF. The alkylation reaction tointroduce R¹ can also be performed on the intermediates described below,prior to implementation of the substituents in 4-quinoline poition byinverting the reaction steps.

[0279] Alternatively, compounds of formula I can be obtained from Ib,according to scheme 2, by an alkylation reaction as above to givecompounds of formula 1c and subsequent Pd catalysed C/O, C/N or C/C bondforming reactions in analogy to known procedures. Thus, substitutedalkoxy, and amino groups can be introduced via a C/O, C/N bond formingreaction under Buchwald conditions, from the corresponding alkohols andamines with, for example, Pd(OAc)₂ as catalyst, BINAP (2,2bis(dipenylphosphino)-1,1-binaphthyl) as chelating phosphine ligand andwith NaOtBu as a base—in a solvent such as toluene and at elevatedtemperature (S. L. Buchwald in: J Am. Chem. Soc. 1996, p. 10333 and Acc.Chem Res. 1998, p 805 for the general method).

[0280] With repect to Pd catalysed C/C bond forming methods to introducethe above defined substituted alkyl and (hetero)aryl groups: This can beachieved via Suzuki-type coupling (for aryl, heteroaryl substitutents)starting from well described or commercial aryl or heteroaryl boronicacids with, for example, Pd(PPh₃)₄ as catalyst, Na₂CO₃ as base, in DMFat elevated temperature (general method: Synth. Commun. 1991, p 513). Analternative consists in using the correponding aryl or heteroarylstannanes in a Stille-type coupling (for general method: Ang. Chem IE,1986, 508).

[0281] Procedures to introduce arylalky, heteroarylalkyl consists ofapplying the reaction discussed above or to use Pd catalysed C/C bondformation under Negishi conditions, starting from the known arylalkyl,heteroarylalkyl Li or Mg salts, with Pd(PPh₃)₄ as catalyst, in thepresence of ZnCl₂ and in THF as solvent (general method: Acc. Chem. Res.1982, p340). Other methods (e.g for arylethyl, heteroarylethyl groupintroduction) consists of performing a Heck-type coupling, starting froma correponding (hetero)aryl olefine and Ic, with Pd₂(dba)₃ as catalyst,P(t-Bu)₃ as phosphine ligand, CsCO₃ as base in DMF as solvent atelevated temperature. (G. C. Fu in: J. Org. Chem. 1999, p. 10 for recentapplication of the reaction). The (hetero)arylalkene condensationproducts can then be reduced further by hydrogenation.

[0282] A method to introduce alkinyl groups consists of reacting analkine with 1c under the Sonogashira conditions (review: Org. Prep.Proceed. Int. 1995, p127) with Pd(PPh₃)₄ as catalyst, in the presence ofCuI and with triethyl amine as a base. Alkenyl dervivatives are obtainedfrom alkenes via Heck coupling as pointed out above, and alkyl as R²substituent can be obtained from the corresponding alkenes byhydrogenation.

[0283] An alternative sequence to perform above discussed Stille-,Negishi and Suzuki-type condensations consisits of performing anhalogen/metal exchange reaction from Ic, to obtain the correpondingstannanes, Li or Mg salts or boronic acids. This is then followed by aPd-catalysed condensation with appropriate halogenides (R²Hal) accordingto the general methods given above.

[0284] R² is halogen, alkyl, alkenyl, alkinyl, aralkyl, heteroarylalkyl,hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl, aryloxy,arylamino, heteroarylamino, NH₂—, mono- or dialkylamino, heterocyclyl,arylalkylamino, heteroarylalkylamino, aryl, heteroaryl, arylalkoxy orheteroarylalkoxy.

[0285] Compounds of formula I can also be prepared according to scheme 3from compounds of formula II with appropriate alkohols (R¹OH) in a Pdcatalysed C/O bond forming reaction under Buchwald conditions asdiscussed above or by Ullman-type rection with, for example CuCl, in asolvent such as DMF, in analogy to a method described by J. A. Ragan:Synthesis 1998, p1599.

[0286] Compounds of formula Ia, b and II can be prepared as follows:

[0287] The preparation of compounds according to formula Ia₁, wherein R³is not NH₂—, alkylamino, dialkylamino or alkoxy, is achieved isaccording to scheme 4, starting from appropriate anilines which areeither known in the literature or which can being prepared by standardprocedures known in the art. Thus, condensation with correspondingalkoxycarbonyl ketones or aldehydes in the presence of p-toluenesulfonicacid, in refluxing cyclohexane and under capture of water producedduring the reaction, the enamine derivatives of formula IV are obtained.Subsequent ring closure is achieved on heating at 250° C. in a highboiling solvent such as Dowtherm A to give compounds of formula V.Transformation to the corresponding chloro quinoline derivatives offormula VI is performed on treatment with POCl₃ under reflux, a standardmethod known in the literature. Subsequent reaction with correspondingamines as defined above, either using a large excess of amine withoutsolvent or on reaction with a 2-fold access, in a suited solvent such asethanol or THF and in the presence of catalytic amounts of NaI and withpyridine as a base, gives compounds of formula VII₁. The amines used areeither substituted with R⁴, R⁵ groups as defined or the groups can beintroduced by functional group conversion as known in the art. P is aprotecting group such as benzyl, ally or tert.butyl. Deprotection understandard conditions known in the art gives rise to Ia₁. Compounds offormula Ia₁ can also be obtained from the corresponding methoxyderivatives (P=Me, formula VII₁) on methyl ether cleavage with BBr₃ inCH₂Cl₂ as a solvent.

[0288] R³ is hydrogen or alkyl;

[0289] P is a protecting group such as e.g. benzyl, allyl or tert.butyl;

[0290] R′ is methyl or ethyl.

[0291] Compounds of formula Ib₁ and II₁ (R³ not NH₂—, alkylamino,dialkylamino or alkoxy) are prepared as described above fromappropriately substituted anilines according to scheme 4.

[0292] Compounds of formula Ia₂, with R³ equaling NH₂—, alkylamino,dialkylamino can be prepared from anilines of formula III, bycondensation with alkyl cyanoacetates, ring closure and subsequentfunctional group transformations as described above. The correspondingcompounds with alkylamino or dialkylamino as R³ substitutents can beobtained from, for example, intermediate IX or V11₂ (R³═NH₂) byselective N-alkylation.

[0293] In analogy to the sequence described in scheme 5 and startingfrom the appropriate anilines there can be obtained the compounds offomula Ib₂ and II₂ (R³ equaling NH₂— or alkylamino or dialkylamino).

[0294] R³ is NH₂—, alkylamino or dialkylamino;

[0295] R′ is methyl or ethyl;

[0296] P is a protecting group such benzyl, allyl or tert.-butyl.

[0297] A further method to prepare compounds of formula Ia₂, Ib₂ and II₂comprises condensation of anilines of formula III with malonic esters togive compounds of formula X. Subsequent ring closure provides the2,4-dihydroxyquinolines of formula XI. Subsequent chlorination withPOCl₃ gives then the 2,4-dichloro-quinolines of formula XII which can beselectively transformed to compounds of type VII₂ by sequentialsubstitution reactions with the corresponding amines—in analogy to knownreactions in the literature. By this procedure there can also beobtained compound of formula VII₂ (R³ is alkoxy) via sequentialtreatment of XII with correponding amines and alkohols . The compoundsIb₂, II₂ can be prepared in analogy according to scheme 6.

[0298] Preferred procedures are according to schemes 1, 2 and 5.

[0299] R³ is NH₂—, alkylamino, dialkyl amino or alkoxy;

[0300] R′ is methyl or ethyl;

[0301] R″ is methyl or ethyl.

[0302] The conversion of a compound of formula I into a pharmaceuticallyacceptable salt can be carried out by treatment of such a compound withan inorganic acid, for example a hydrohalic acid, such as, for example,hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid etc., or with an organic acid, such as, for example,acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid,methanesulfonic acid or p-toluenesulfonic acid. The correspondingcarboxylate salts can also be prepared from the compounds of formula Iby treatment with physiologically compatible bases.

[0303] The conversion of compounds of formula I into pharmaceuticallyusable esters or amides can be carried out e.g. by treatment of suitedamino or hydroxyl groups present in the molecules with an carboxylicacid such as acetic acid, with a condensating reagent such asbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) or N,N-dicylohexylcarbodiimide (DCCI) to produce the carboxylicester or carboxylic amide.

[0304] A preferred process for the preparation of a compound of formulaI comprises one of the following reactions:

[0305] a) reaction of a compound of the formula Ia in the presence of acompound of the formula R¹-Hal

[0306] wherein R¹, R², R³, R⁴, R⁵ and A are as defined before and Hal ishalogen; or

[0307] b) Pd catalyzed C/O, C/N or C/C bond forming reaction of acompound of formula Ic in order to obtain a compound of formula I

[0308] wherein R¹, R², R³, R⁴, R⁵ and A are defined as before and Hal ishalogen, preferably chloro, bromo or iodo. Preferred is the reaction ofa compound according to formula Ic under Buchwald conditions (S. L.Buchwald in: J Am. Chem. Soc. 1996, p. 10333 and Acc. Chem Res. 1998, p805 for the general method), particularly in the presence of Pd(OAc)₂,BINAP and a base such as NaOtBu with a corresponding alkohol or amine inorder to form a compound of formula I, wherein R² means alkoxy or amino.Further preferred is the reaction of a compound of formula Ic underSuzuki-type coupling conditions (general method: Synth. Commun. 1991, p513) in the presence of corresponding arylboronic acids orheteroarylboronic acids in order to form a compound of formula I,wherein R² means aryl or heteroaryl. Also preferred is the reaction of acompound of formula Ic under Stille coupling conditions (for generalmethod: Ang. Chem IE, 1986, 508) in the presence of correspondingarylstannanes or heteroarylstannanes in order to form a compound offormula I, wherein R² means aryl or heteroaryl. Further preferred is thereaction of a compound of formula Ic under Sonogashira conditions(review: Org. Prep. Proceed. Int. 1995, pl27), particularly in thepresence of CuI and a base such as triethylamine in the presence ofcorresponding alkines in order to form a compound of formula I, whereinR² means alkinyl; or

[0309] c) a halogen/metal exchange reaction of a compound of formula Icas defined in step b) and subsequent Pd catalyzed condensation with ahalogenide of the formula R²-Hal to yield a compound of formula I,wherein R¹, R³, R⁴, R⁵ and A are as defined as before, Hal is halogenand R² is alkenyl, alkinyl, alkoxy, alkoxyalkoxy, aryloxy, arylamino,heteroarylamino, NH₂—, monoalkylamino, dialkylamino, arylalkylamino,heteroarylalkylamino, aryl, arylalkoxy or heteroarylalkoxy; or

[0310] d) reaction of a compound of formula II in the presence of analcohol of the formula R¹—OH and a palladium catalyst in order to obtaina compound of formula I

[0311] wherein R², R³, R⁴, R⁵ and A are defined as before, Hal ishalogen and R¹ is hydrogen, alkyl, alkoxyalkyl, alkenyl, alkinyl,hydroxyalkyl, aralkyl, heterocyclylalkyl, cycloalkylalkyl, NH₂—SO₂—,monoalkylamino-SO₂—, dialkylamino-SO₂—, alkyl-SO₂—, aryl, NH₂-alkyl,monoalkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylalkyl,carboxyalkyl, aryl-SO₂—O-alkyl, cycloalkyl or cycloalkylalkyl.

[0312] A particularly preferred process for the preparation of acompound of formula I comprises one of the reactions a), c) or d) asmentioned before.

[0313] Preferred intermediates are:

[0314] 7-benzyloxy-4-chloro-2-methyl-quinoline;

[0315] 7-benzyloxy-6-butyl-4-chloro-quinoline hydrochloride;

[0316] 6-bromo-4-chloro-7-methoxy-2-methyl-quinoline.

[0317] The compounds of formula I described above for use astherapeutically active substances are a further object of the invention.

[0318] Also an object of the invention are compounds described above forthe production of medicaments for the prophylaxis and therapy ofillnesses which are caused by disorders associated with the NPYreceptor, particularly for the production of medicaments for theprophylaxis and therapy of arthritis, cardiovascular diseases, diabetes,renal failure and particularly eating disorders and obesity.

[0319] Likewise an object of the invention are pharmaceuticalcompositions containing a compound of formula I described above and atherapeutically inert carrier.

[0320] An object of the invention is also the use of the compoundsdescribed above for the production of medicaments, particularly for thetreatment and prophylaxis of arthritis, cardiovascular diseases,diabetes, renal failure and particularly eating disorders and obesity.

[0321] A further object of the invention comprises compounds which aremanufactured according to one of the described processes.

[0322] A further object of the invention is a method for the treatmentand prophylaxis of arthritis, cardiovascular diseases, diabetes, renalfailure and particularly eating disorders and obesity whereby aneffective amount of a compound described above is administered.

[0323] According to a further aspect of the invention there is provideda method of treatment of obesity in a human in need of such treatmentwhich comprises administration to the human a therapeutically effectiveamount of a compound according to formula I and a therapeuticallyeffective amount of a lipase inhibitor, particularly preferred, whereinthe lipase inhibitor is orlistat. Also subject of the present inventionis the mentioned method, wherein the administration is simultaneous,separate or sequential.

[0324] A further preferred embodiment of the present invention is theuse of a compound of the formula I in the manufacture of a medicamentfor the treatment and prevention of obesity in a patient who is alsoreceiving treatment with a lipase inhibitor, particularly preferred,wherein the lipase inhibitor is orlistat.

Assay Procedures Cloning of Mouse NPY5 Receptor cDNAs

[0325] The full-length cDNA encoding the mouse NPY5 (mNPY5) receptor wasamplified from mouse brain cDNA using specific primers, designed basedon the published sequence, and Pfu DNA-Polymerase (Stratagene). Theamplification product was subcloned into the mammalian expression vectorpcDNA3 using Eco RI and XhoI restriction sites. Positive clones weresequenced and one clone, encoding the published sequence was selectedfor generation of stable cell clones.

Stable Transfection

[0326] Human embryonic kidney 293 (HEK293) cells were transfected with10 μg mNPY5 DNA using the lipofectamine reagent (Gibco BRL) according tothe manufacturer's instruction. Two days after transfection, geneticinselection (1 mg/ml) was initiated and several stable clones wereisolated. One clone was further used for pharmacologicalcharacterization.

Radioligand Competition Binding

[0327] Human embryonic kidney 293 cells (HEK293), expressing recombinantmouse NPY5-receptor (mNPY5) were broken by three freeze/thawing cyclesin hypotonic Tris buffer (5 mM, pH 7.4, 1 mM MgCl₂), homogenized andcentrifuged at 72,000× g for 15 min. The pellet was washed twice with 75mM Tris buffer, pH 7.4, containing 25 mM MgCl₂ and 250 mM sucrose, 0.1mM phenylmethylsulfonylfluoride and 0.1 mM 1,10-pheneanthrolin,resuspended in the same buffer and stored in aliquots at −80° C. Proteinwas determined according to the method of Lowry using bovine serumalbumine (BSA) as a standard.

[0328] Radioligand competition binding assays were performed in 250 μl25 mM Hepes buffer (pH 7.4, 2.5 mM CaCl₂, 1 mM MgCl₂, 1% bovine serumalbumine, and 0.01% NaN₃ containing 5 μg protein, 100 pM [¹²⁵I]labelledpeptide YY (PYY) and 10 μL DMSO containing increasing amounts ofunlabelled test compounds. After incubation for 1 h at 22° C., bound andfree ligand are separated by filtration over glass fibre filters. Nonspecific binding is assessed in the presence of 1 μM unlabelled PYY.Specific binding is defined as the difference between total binding andnon specific binding. IC₅₀ values are defined as the concentration ofantagonist that displaces 50% of the binding of [¹²⁵I]labelledneuropeptide Y. It is determined by linear regression analysis afterlogit/log transformation of the binding data.

[0329] Results obtained in the foregoing test using representativecompounds of the invention as the test compounds are shown in thefollowing table: NPY5-R (mouse) Compound IC₅₀ (nM)7-cyclopropylmethoxy-2- 27 methyl-4-pyrrolidin-1-yl- quinoline (example5) 6-butyl-4-pyrrolidin-1-yl- 9.9 quinolin-7-ol (example 34)

[0330] Preferred compounds as described above have IC₅₀ values below1000 nM; more preferred compounds have IC₅₀ values below 100 nM,particularly below 10 nM. Most preferred compounds have IC₅₀ valuesbelow 2 nM. These results have been obtained by using the foregoingtest.

[0331] The compounds of formula I and their pharmaceutically usablesalts and esters can be used as medicaments (e.g. in the form ofpharmaceutical preparations). The pharmaceutical preparations can beadministered internally, such as orally (e.g. in the form of tablets,coated tablets, dragées, hard and soft gelatin capsules, solutions,emulsions or suspensions), nasally (e.g. in the form of nasal sprays) orrectally (e.g. in the form of suppositories). However, theadministration can also be effected parentally, such as intramuscularlyor intravenously (e.g. in the form of injection solutions).

[0332] The compounds of formula I and their pharmaceutically usablesalts and esters can be processed with pharmaceutically inert, inorganicor organic adjuvants for the production of tablets, coated tablets,dragées and hard gelatin capsules. Lactose, corn starch or derivativesthereof, talc, stearic acid or its salts etc. can be used, for example,as such adjuvants for tablets, dragées and hard gelatin capsules.

[0333] Suitable adjuvants for soft gelatin capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

[0334] Suitable adjuvants for the production of solutions and syrupsare, for example, water, polyols, saccharose, invert sugar, glucose,etc.

[0335] Suitable adjuvants for injection solutions are, for example,water, alcohols, polyols, glycerol, vegetable oils, etc.

[0336] Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0337] Moreover, the pharmaceutical preparations can containpreservatives, solubilizers, viscosity-increasing substances,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorants, salts for varying the osmotic pressure, buffers, maskingagents or antioxidants. They can also contain still othertherapeutically valuable substances.

[0338] In accordance with the invention the compounds of formula I andtheir pharmaceutically usable salts can be used for the prophylaxis andtreatment of arthritis, cardiovascular diseases, diabetes, renal failureand particularly eating disorders and obesity. The dosage can vary inwide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 0.1 mg to 20 mg per kg bodyweight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about300 mg per person), divided into preferably 1-3 individual doses, whichcan consist, for example, of the same amounts, should be appropriate. Itwill, however, be clear that the upper limit given above can be exceededwhen this is shown to be indicated.

[0339] The invention is illustrated hereinafter by Examples, which haveno limiting character.

EXAMPLES Example 1

[0340] a) A mixture of 534 mg (1.8 mmol) of7-benzyloxy-4-chloro-2-methyl-quinoline and 3.77 ml (45 mmol)pyrrolidine was heated at 80° C. (oil bath temperature) under an argonatmosphere for 23 h after which time the reaction was completedaccording to HPLC analysis. The reaction was partitioned between EtOAcand water, the aqueous layer was extracted once with EtOAc, the combinedorganic layers were washed with water then saturated NaCl solution,dried over magnesium sulphate and concentrated in vacuo. The residue wasapplied to silica gel column with CH₂Cl₂/MeOH/NH₄OH (19:1:0.05) aseluent. Combination of the purified fractions and concentration in vacuogave 430 mg (74.5%) of the7-benzyloxy-2-methyl-4-pyrrolidin-1-yl-quinoline as a brown solid. ISPmass spectrum, m/e: 319.4 (M+1 calculated for C₂₁H₂₂N₂O: 319).

[0341] Preparation of the Starting Material:

[0342] b) 20 g (98.4 mmol)of 3-benyloxyaniline, 12.6 ml (0.984 mmol) ofethyl acetoacetate and 0.189 g (1 mmol) of p-toluenesulfonic acidmonohydrate in 32 ml of cyclohexane were heated at reflux for 5.5 h inthe presence of a water separator funnel. The reaction mixture wascooled to RT, some solid material was filtered off by suction and thefiltrate was concentrated in vacuo to give 30.6 g (99%) of the desired3-(3-benzyloxy-phenylamino)-but-2-enoic acid ethyl ester as a yellowoil. This was used without further purification in the next reactionstep.

[0343] c) 3.67 g (11.8 mmol) of 3-(3-benzyloxy-phenylamino)-but-2-enoicacid ethyl ester were added dropwise within 20 minutes to 5.5 ml ofDowtherm A heated at 250° C. (metal bath temperature). The solution wasstirred further 10 minutes at 250° C. (bath temperature), cooled to RTand then treated with 20 ml of heptane. The brown viscous oil that hadformed was isolated and triturated with 45 ml of AcOEt. The brown solidobtained was filtered off by suction, washed with AcOEt and dried in ahigh vacuum to give 1.19 g (35%) of 7-benzyloxy-2-methyl-quinolin-4-ol.ISP mass spectrum, m/e: 266.3 (M+1 calculated for C₁₇H₁₅NO₂: 266).

[0344] d) 1.15 g (3.99 mmol) of 7-benzyloxy-2-methyl-quinolin-4-ol in7.46 ml (79.8 mmol) of POCl₃ were heated at 130° C. (oil bathtemperature) for 1h 40 min until completion of the reaction according toTLC analysis. The reaction mixture was cooled to RT and the solvent wasremoved in vacuo. The residue was taken up in ice water and stirred for2 h. The pH was adjusted to values between pH 9-10 with concentratedNH₄Cl, the brown solid which precipitated was filtered off by suction,washed with water and subsequently dried in a high vacuum. This gave 1 g(84.5%) of 7-benzyloxy-4-chloro-2-methyl-quinoline as a brown solid. Elmass spectrum, m/e: 283.1 (M+1 calculated for C₁₇H₁₄ClNO: 283).

Example 2

[0345] A solution of 13 g of7-benzyloxy-2-methyl-4-pyrrolidin-1-yl-quinoline, product of example 1,dissolved in 750 ml of MeOH was treated with 4 g of palladium oncharcoal (10%) and then hydrogenated at RT for 1.5 h until HPLC analysisindicated the completion of the reaction. The catalyst was filtered off,washed with water) and the solution was concentrated in vacuo. The solidthat precipitated was collected by filtration and dried in a high vacuumto give 8.9 g (96.2%) of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol as anamorphous yellow solid. ISP mass spectrum, m/e: 229.2 (M+1 calculatedfor C₁₄H₁₆N₂O: 229).

Example 3

[0346] 229.4 mg (1 mmol) of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol,product of example 2, were suspended under an argon atmosphere in 20 mlof DMF, 0.6 g (1.2 mmol) of molecular sieves (4 nm) were added followedby 138 mg (1.2 mmol) of potassium tert-butoxide, and the mixture wasstirred for 1 h at RT. It was then cooled to 0° C., treated with 0.13 ml(1.2 mmol) N,N-dimethylsulfamoyl chloride and stirred for 3 h at 0° C.The reaction mixture was partitioned between EtOAc and water, theaqueous layer was extracted twice with EtOAc, the combined organiclayers were washed with water then with saturated NaCl solution, driedover magnesium sulphate and concentrated in vacuo. The residue wastriturated with diethyl ether; the viscous oil obtained was filtered offby suction and dried in a high vacuum. Upon further triturating withheptane solid material was obtained which was dried in a high vacuum togive 100 mg (29.3%) of dimethyl-sulfamic acid2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl ester as an off-white solid.ISP mass spectrum, m/e: 336.2 (M+1 calculated for C₁₆H₂₁N₃O₃S: 336).

Example 4

[0347] In analogy to example 3, from2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 2, andmethanesulfonyl chloride there was obtained methanesulfonic acid2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl ester as an off-white solid.ISP mass spectrum, m/e: 307.3 (M+1 calculated for C₁₅H₁₈N₃O₃S: 307).

Example 5

[0348] In analogy to example 3, from2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 2, andcyclopropylmethyl bromide—with reaction times of 19 h (0° C.) andisolation of the product as hydrochloride, via treatment of the reactionproduct with HCl-saturated diethyl ether—there was obtained7-cyclopropylmethoxy-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochlorideas a white solid. ISP mass spectrum, m/e: 283.2 (M+1 calculated forC₁₈H₂₂N₂O: 283).

Example 6

[0349] A mixture of 114 mg (0.5 mmol) of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 2, 166 mg(0.6 mmol) of potassium carbonate and 84 μl (0.6 mmol) of3-methoxybenzyl chloride was heated at 80° C. in 8 ml of DMF under anargon atmosphere for 23 h. The mixture was cooled to RT and partitionedbetween EtOAc and water. The organic layer was separated, washed withwater then saturated NaCl solution, dried over magnesium sulphate andconcentrated in vacuo. The residue was taken up in diethyl ether andsome not dissolved material was removed by filtration. The filtrate wastreated under stirring with 0.25 ml of 3N HCL in MeOH and stirring wascontinued for 1 h. The solid that precipitated was filtered off bysuction and dried in a high vacuum to give 138 mg (69.7%) of7-(3-methoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as an light-yellow solid. ISP mass spectrum, m/e: 349.4(M+1 calculated for C₂₂H₂₄N₂O₂: 349).

Example 7

[0350] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with methyl iodide,7-methoxy-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride as anoff-white solid. ISP mass spectrum, m/e: 243.3 (M+1 calculated forC₁₅H₁₈N₂O: 243).

Example 8

[0351] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 2-picolyl choride, wherebythe product was isolated as free base,2-methyl-7-(pyridin-2-ylmethoxy)-4-pyrrolidin-1-yl-quinoline as a lightbrown solid. ISP mass spectrum, m/e: 320.4 (M+1 calculated forC₂₀H₂₁N₃O: 320).

Example 9

[0352] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with allyl bromide, whereby theproduct was isolated as free base,7-allyloxy-2-methyl-4-pyrrolidin-1-yl-quinoline as a light yellow solid.EI mass spectrum, m/e: 268.2 (M calculated for C₁₇H₂₀N₂O: 268).

Example 10

[0353] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with isobutyl bromide,7-isobutoxy-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride as awhite solid. ISP mass spectrum, m/e: 285.3 (M+1 calculated forC₁₈H₂₄N₂O: 285).

Example 11

[0354] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 2-methoxybenzyl chloride,7-(2-methoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as an off-white solid. ISP mass spectrum, m/e: 349.4 (M+1calculated for C₂₂H₂₄N₂O₂: 349).

Example 12

[0355] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with tetrahydro-furfurylbromide, whereby the product was isolated as free base, (rac)2-methyl-4-pyrrolidin-1-yl-7-(tetrahydro-furan-2-ylmethoxy)-quinoline asa yellow-brown waxy solid. ISP mass spectrum, m/e: 313.2 (M+1 calculatedfor C₁₉H₂₄N₂O₂: 313).

Example 13

[0356] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with of 4-methoxybenzylchloride, 7-(4-methoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as a light-yellow solid. ISP mass spectrum, m/e: 349.4(M+1 calculated for C₂₂H₂₄N₂O₂: 349).

Example 14

[0357] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 2-bromomethylbenzonitrile, whereby the product was isolated as free base,2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile as abrown solid. ISP mass spectrum, m/e: 344.4 (M+1 calculated forC₂₂H₂₁N₃O: 344).

Example 15

[0358] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 4-bromomethyl benzonitrilewhereby the product was isolated as free base,4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile as abrown solid. ISP mass spectrum, m/e: 344.4 (M+1 calculated forC₂₂H₂₁N₃O: 344).

Example 16

[0359] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 2-(trifluoromethyl)-benzylchloride,2-methyl-4-pyrrolidin-1-yl-7-(2-trifluoromethyl-benzyloxy)-quinolinehydrochloride as a white solid. ISP mass spectrum, m/e: 387.4 (M+1calculated for C₂₂H₂₁F₃N₂O₂: 387).

Example 17

[0360] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with of3-(trifluoromethyl)-benzyl chloride,2-methyl-4-pyrrolidin-1-yl-7-(3-trifluoromethyl-benzyloxy)-quinolinehydrochloride as an off-white solid. ISP mass spectrum, m/e: 387.4 (M+1calculated for C₂₂H₂₁F₃N₂O₂: 387).

Example 18

[0361] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with of4-(trifluoromethyl)-benzyl chloride,2-methyl-4-pyrrolidin-1-yl-7-(4-trifluoromethyl-benzyloxy)-quinolinehydrochloride as an off-white solid. ISP mass spectrum, m/e: 387.4 (M+1calculated for C₂₂H₂₁F₃N₂O₂: 387).

Example 19

[0362] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 2-chlorobenzyl chloride,7-(2-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as a white solid. ISP mass spectrum, m/e: 353.3 (M+1calculated for C₂₁H₂₁ClN₂O: 353).

Example 20

[0363] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 3-chlorobenzyl chloride,7-(3-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as a light-yellow solid. ISP mass spectrum, m/e: 353.3(M+1 calculated for C₂₁H₂₁ClN₂O: 353).

Example 21

[0364] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 4-chlorobenzyl chloride,7-(4-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as an off-white solid. ISP mass spectrum, m/e: 353.3 (M+1calculated for C₂₁H₂₁ClN₂O: 353).

Example 22

[0365] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 3-(chloromethyl)pyridinehydrochloride, whereby the product was isolated as free base,2-methyl-7-(pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinoline as a redsolid. ISP mass spectrum, m/e: 320.4 (M+1 calculated for C₂₂H₂₁N₃O:320).

Example 23

[0366] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 3-bromomethylbenzonitrile, whereby the product was isolated as free base,3-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile as ayellow solid. ISP mass spectrum, m/e: 344.4 (M+1 calculated forC₂₂H₂₁N₃O: 344).

Example 24

[0367] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 2-bromopropane,7-isopropoxy-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride as alight-yellow solid. ISP mass spectrum, m/e: 271.4 (M+1 calculated forC₁₇H₂₂N₂O: 271).

Example 25

[0368] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 1-bromo-2-methoxyethane,7-(2-methoxy-ethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochlorideas a light-brown solid. ISP mass spectrum, m/e: 287.2 (M+1 calculatedfor C₁₇H₂₂N₂O₂: 287).

Example 26

[0369] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with4-(2-chloroethyl)-morpholine hydrochloride, whereby the product wasisolated as free base,2-methyl-7-(2-morpholin-4-yl-ethoxy)-4-pyrrolidin-1-yl-quinoline as abrown solid. ISP mass spectrum, m/e: 342.3 (M+1 calculated forC₂₀H₂₇N₃O₂: 342).

Example 27

[0370] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 4-(chloromethyl)pyridinehydrochloride,2-methyl-7-(pyridin-4-ylmethoxy)-4-pyrrolidin-1-yl-quinolinehydrochloride as a light-yellow solid. ISP mass spectrum, m/e: 320.4(M+1 calculated for C₂₀H₂₁N₃O: 320).

Example 28

[0371] a) A mixture of 436 mg (1.5 mmol) of7-Benzyloxy-4-chloro-2-methyl-quinoline, product of example 1d), and1.75 g (15 mmol) of (S)-3-ethoxypyrrolidine, prepared according toTetrahedron Lett., 1995, 2745, was heated at 80° C. (oil bathtemperature) under an argon atmosphere for 18 h after which time thereaction was completed according to HPLC analysis. The excess(S)-3-ethoxy-pyrrolidine was distilled off, and the residue waspartitioned between EtOAc and water. The layers were separated, theorganic layer was washed with water then saturated NaCl solution, driedover magnesium sulphate and concentrated in vacuo. The residue wastaken-up in MeOH (1 ml) diluted with diethyl ether (30 ml) and thentreated dropwise at RT under stirring with 0.7 ml of 3N HCL in MeOH. Thesolvent was removed and the remaining salt triturated with diethylether, then filtered off by suction and dried in a high vacuum to give425 mg (69.7%) of the(S)-7-benzyloxy-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolinehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 363.2(M+1 calculated for C₂₃H₂₆N₂O₂: 363).

Example 29

[0372] A solution of 93 mg (0.23 mmol) of(S)-7-Benzyloxy-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolinehydrochloride, product of example 28, dissolved in 7 ml of MeOH wastreated with 48 mg of palladium on charcoal (10%) and then hydrogenatedat RT for 1.5 h until HPLC analysis indicated the completion of thereaction. The catalyst was filtered off, washed with water, and thesolution was concentrated in vacuo. The residue was triturated with nhexane/diethyl ether, the solid obtained was filtered off by suction anddried in a high vacuum to give 67 mg (90%) of(S)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol hydrochloride asan off-white solid. ISP mass spectrum, m/e: 273.3 (M+1 calculated forC₁₆H₂₀N₂O₂: 273).

Example 30

[0373] In analogy to example 6, on reaction of(S)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol hydrochloride,product of example 29, with 3-methoxybenzyl chloride there was obtained:(S)-4-(3-ethoxy-pyrrolidin-1-yl)-7-(3-methoxy-benzyloxy)-2-methyl-quinolinehydrochloride as a white solid. ISP mass spectrum, m/e: 393.3 (M+1calculated for C₂₄H₂₈N₂O₃: 393).

Example 31

[0374] In analogy to example 6, on reaction of(S)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol hydrochloride,product of example 29, with 4-bromomethyl benzonitrile there wasobtained:(S)-4-[4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrilehydrochloride as a yellow solid. ISP mass spectrum, m/e: 388.3 (M+1calculated for C₂₄H₂₅N₃O₂: 388).

Example 32

[0375] In analogy to example 6, on reaction of(S)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol hydrochloride,product of example 29, with 2-bromomethyl benzonitrile there wasobtained:(S)-2-[4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrilehydrochloride as a light-orange solid. ISP mass spectrum, m/e: 388.3(M+1 calculated for C₂₄H₂₅N₃O₂: 388).

Example 33

[0376] a) A solution of 1 g (3.07 mmol) of7-benzyloxy-6-butyl-4-chloro-quinoline hydrochloride in 2.5 ml (30.7mmol) of pyrrolidine was heated at 60° C. with stirring under an argonatmosphere for 24 h after which time the reaction was completedaccording to HPLC analysis. The excess pyrrolidine was evaporated off,and the residue was partitioned between EtOAc and water. The layers wereseparated and the aqueous layer once extracted with AcOEt. The combinedorganic layers were washed with water then saturated NaCl solution,dried over magnesium sulphate and concentrated in vacuo to give 1.12 g(97.4%) of the 7-benzyloxy-6-butyl-4-pyrrolidin-1-yl-quinoline as abrown oil. ISP mass spectrum, m/e: 361.3 (M+1 calculated for C₂₄H₂₈N₂O:361).

[0377] Preparation of the Starting Material:

[0378] b) A suspension of 1.75 g (5 mmol)of7-benzyloxy-6-butyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid(prepared from methyl benzoquate on ester hydrolysis with KOH inEtOH—H₂O) in 9 ml of quinoline was treated with 57 mg (0.9 mmol) of Cupowder and heated for 1 h at 200° C. The black reaction mixture wascooled to RT, 80 ml of diethyl ether were added and the solid whichprecipitated was filtered off by suction. It was then taken up in 100 mlof MeOH, heated to reflux and filtered hot. The filtrate was thenconcentrated in vacuo. The residue was triturated with diethyl ether,filtered off by suction and dried in a high vacuum to give 966 mg (63%)of the 7-benzyloxy-6-butyl-1H-quinolin-4-one as a light-yellow solid.ISP mass spectrum, m/e: 308.3 (M+1 calculated for C₂₀H₂₁NO₂: 308).

[0379] c) A suspension of 900 mg (2.93 mmol) of7-benzyloxy-6-butyl-1H-quinolin-4-one in 1.44 ml of POCl₃ (15.8 mmol)was treated with 0.074 ml of N,N-dimethylaniline and heated at 60° C.for 3 h with stirring. The reaction mixture was then poured into icewater and stirred for 0.5 h. The solid which precipitated was filteredoff by suction washed with water and dried in a high vacuum to give 1.05g (99%) of 7-benzyloxy-6-butyl-4-chloro-quinoline hydrochloride as lightgray solid. ISP mass spectrum, m/e: XX (M+1 calculated for C₂₀H₂₀ClNO:325.84).

Example 34

[0380] A solution of 1.02 g (2.83 mmol) of the7-benzyloxy-6-butyl-4-pyrrolidin-1-yl-quinoline, product of example 33,dissolved in 50 ml of MeOH was treated with 0.33 g of palladium oncharcoal (10%) and then hydrogenated at RT for 2 h until TLC analysisindicated the completion of the reaction. The catalyst was filtered off,the solution was concentrated in vacuo and the residue was dried in ahigh vacuum to give 0.65 g (82%) of the6-butyl-4-pyrrolidin-1-yl-quinolin-7-ol as a light yellow solid. ISPmass spectrum, m/e: 271.3 (M+1 calculated for C₁₇H₂₂N₂O: 271).

Example 35

[0381] In analogy to example 6, on reaction of6-butyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 34, withmethyl iodide chloride there was obtained:6-butyl-7-methoxy-4-pyrrolidin-1-yl-quinoline hydrochloride as a waxybrown solid. ISP mass spectrum, m/e: 285.3 (M+1 calculated forC₁₈H₂₄N₂O: 285).

Example 36

[0382] In analogy to example 6, on reaction of6-butyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 34, withethyl iodide chloride there was obtained:6-butyl-7-ethoxy-4-pyrrolidin-1-yl-quinoline hydrochloride as anamorphous yellow solid. ISP mass spectrum, m/e: 299.4 (M+1 calculatedfor C₁₉H₂₆N₂O: 299).

Example 37

[0383] In analogy to example 6, on reaction of6-butyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 34, withbromomethyl cyclopropane there was obtained:6-butyl-7-cyclopropylmethoxy-4-pyrrolidin-1-yl-quinoline hydrochlorideas an off-white solid. ISP mass spectrum, m/e: 325.3 (M+1 calculated forC₂₁H₂₈N₂O: 325).

Example 38

[0384] In analogy to example 6, on reaction of6-butyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 34,4-bromomethyl benzonitrile there was obtained:4-(6-butyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile as alight yellow solid. ISP mass spectrum, m/e: 386.4 (M+1 calculated forC₂₅H₂₇N₃O: 386).

Example 39

[0385] A solution of 2 g (6.9 mmol) of7-benzyloxy-4-chloro-2-methyl-quinoline, product of example 1d), in 15.5ml (0.137 mol) of hexamethyleneimine was heated at 120° C. (oil bathtemperature) with stirring under an argon atmosphere for 100 h afterwhich time the reaction was completed according to HPLC analysis. Thereaction mixture was cooled to RT and then partitioned between EtOAc andwater. The layers were separated the aqueous layer once extracted withAcOEt. The combined organic layers were washed with water then saturatedNaCl solution, dried over magnesium sulphate and concentrated in vacuo.The oily residue was dissolved in a small amount of MeOH and treatedunder stirring with 4 ml of 3N HCl in MeOH. The solvent was removed invacuo, the residue triturated with diethyl ether under stirring for 1.5h and the obtained solid filtered off by suction and dried in a highvacuum. (Further material was obtained on evaporation of the filtrateand treatment of the residue as described above). The desired4-azepan-1-yl-7-benzyloxy-2-methyl-quinoline hydrochloride, 1.46 g(55.2%) was thus obtained as a light brown solid. ISP mass spectrum,m/e: 347.4 (M+1 calculated for C₂₃H₂₆N₂O: 347).

Example 40

[0386] A solution of 1.45 g (3.78 mmol) of4-azepan-1-yl-7-benzyloxy-2-methyl-quinoline hydrochloride, product ofexample 39, dissolved in 120 ml of MeOH was treated with 700 mg ofpalladium on charcoal (10%) and then hydrogenated at RT for 2 h untilHPLC analysis indicated the completion of the reaction. The catalyst wasfiltered off, washed with water, and the solution was concentrated invacuo. The residue was triturated with diethyl ether, the solid obtainedwas filtered off by suction and dried in a high vacuum to give 1 g(90.4%) 4-azepan-1-yl-2-methyl-quinolin-7-ol hydrochloride as a lightgray solid. ISP mass spectrum, m/e: 257.2 (M+1 calculated for C₁₆H₂₀N₂O:257).

Example 41

[0387] In analogy to example 6, on reaction of4-azepan-1-yl-2-methyl-quinolin-7-ol hydrochloride, product of example40, with 4-(chloromethyl)pyridine hydrochloride there was obtained:4-azepan-1-yl-2-methyl-7-(pyridin-4-ylmethoxy)-quinoline hydrochlorideas a light yellow solid. ISP mass spectrum, m/e: 348.4 (M+1 calculatedfor C₂₂H₂₅N₃O: 348).

Example 42

[0388] In analogy to example 6, on reaction of4-azepan-1-yl-2-methyl-quinolin-7-ol hydrochloride, product of example40, with 4-bromomethyl benzonitrile there was obtained:4-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrilehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 372.3(M+1 calculated for C₂₄H₂₅N₃O: 373).

Example 43

[0389] In analogy to example 6, on reaction of4-azepan-1-yl-2-methyl-quinolin-7-ol hydrochloride, product of example40, with 3-bromomethyl benzonitrile there was obtained:3-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrilehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 372.3(M+1 calculated for C₂₄H₂₅N₃O: 373).

Example 44

[0390] In analogy to example 6, on reaction of4-azepan-1-yl-2-methyl-quinolin-7-ol hydrochloride, product of example40, with 2-(chloromethyl)pyridine hydrochloride there was obtained:4-azepan-1-yl-2-methyl-7-(pyridin-2-ylmethoxy) -quinoline hydrochlorideas a light yellow solid. ISP mass spectrum, m/e: 348.5 (M+1 calculatedfor C₂₂H₂₅N₃O: 348).

Example 45

[0391] a) A suspension of 1 g (3.5 mmol) of6-bromo-4-chloro-7-methoxy-2-methyl-quinoline in 20 ml of EtOH wastreated sequentially at RT and under stirring with 0.49 g (7 mmol) ofpyrrolidine, 0.137 g (1.4 mmol) of pyridine and a catalytic amount ofNaI. The mixture was then heated to reflux for 20 h, cooled to RT andconcentrated in vacuo. The residue was applied to a silica gel columnwith CH₂Cl₂/MeOH (7:1) as eluent. Combinations of the purified fractionsand concentration in vacuo gave 0.85 g (68.2%) of the6-bromo-7-methoxy-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride aslight brown solid. ISP mass spectrum, m/e: 323.3 (M+1 calculated forC₁₅H₁₇BrN₂O: 323).

[0392] Preparation of the Starting Material:

[0393] b) 7.66 g (37.9 mmol) of 4-bromo-3-methoxy-phenylamine(preparation described in Tetrahedron Lett., 1995, 7583) were dissolvedin 80 ml of cyclohexane at 70° C. and subsequently treated understirring with 72 mg (0.38 mmol) of p-toluenesulfonic acid monohydrateand 4.93 g (37.9 mmol) of ethyl acetoacetate. The solution was thenheated at reflux for 3.5 h with a water separator funnel connected. Itwas then cooled to RT and concentrated in vacuo. The residue was appliedto a silica gel column with hexane/diethyl ether (3:1) as eluent.Combinations of the purified fractions and concentration in vacuo gave8.2 g (68.8%) of the (Z)-3-(4-bromo-3-methoxy-phenylamino)-but-2-enoicacid ethyl ester, as a yellow solid. ISP mass spectrum, m/e: 316.2(M+1calculated for C₁₃H₁₆BrNO₃: 316).

[0394] c) A suspension of 6.6 g (21 mmol) of(Z)-3-(4-bromo-3-methoxy-phenylamino)-but-2-enoic acid ethyl ester in 40ml of Dowtherm A were heated under stirring at 220° C. for 7.5 h afterwhich time TLC analysis indicated completion of the reaction. Themixture was cooled to RT under stirring and the solvent was decantedoff. The remaining solid residue was triturated with hexane, filteredoff by suction and dried in a high vacuum to give 4.7 g (84%) of the6-bromo-7-methoxy-2-methyl-quinolin-4-ol as a dark brown solid. EI massspectrum, m/e: 269 (M calculated for C₁₁H₁₀BrNO₂: 269).

[0395] d) A suspension of 4.6 g (17.5 mmol) of6-bromo-7-methoxy-2-methyl-quinolin-4-ol in 14.8 ml (158 mmol) of POCl₃was heated at 60° C. for 20 h with stirring. It was then cooled to RTand 50 ml of diethyl ether were added. The solid that precipitated wasfiltered off by suction and dried in a high vacuum to give 3.85 g of the6-bromo-4-chloro-7-methoxy-2-methyl-quinoline as a dark brown solid. Elmass spectrum, m/e: 287 (M calculated for C₁₁H₉BrClNO: 287).

Example 46

[0396] A solution of 115 mg (0.32 mmol) of6-bromo-7-methoxy-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride,compound of example 45 a), was dissolved in 5 ml of dry CH₂Cl₂ under anargon atmosphere and treated dropwise with 0.16 g (0.64 mmol) of 1M BBr₃in CH₂Cl₂ with ice cooling. After 0.5 h the ice bath was removed, thesolution was stirred for 2 h at RT and then heated to reflux for 12 h.The reaction mixture was cooled to RT and partitioned between ice waterand CH₂Cl₂. The layers were separated, the aqueous layer furtherextracted with CHCl2/MeOH mixtures (8:1).

[0397] The combined organic layers were dried over magnesium sulphateand concentrated in vacuo. The residue was applied to a silica gelcolumn with CH₂Cl₂/MeOH (15:1) as eluent. Combinations of the purifiedfractions and concentration in vacuo gave 39 mg (35%) of the6-bromo-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol hydrochloride as alight brown solid. ISP mass spectrum, m/e: 307.2 (M+1 calculated forC₁₄H₁₅BrN₂O: 307).

Example 47

[0398] In analogy to example 6, on reaction6-bromo-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol hydrochloride, productof example 46, with 4-bromomethyl benzonitrile there was obtained:4-(6-bromo-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrileas a light yellow solid. ISP mass spectrum, m/e: 424.3 (M+1 calculatedfor C₂₂H₂₀BrN₃O: 424).

Example 48

[0399] a) A solution of 319 mg (0.92 mmol) of4-chloro-7-methoxy-quinolin-2-ylamine in 20 ml of isopropanol wastreated with 130 mg (1.83 mmol) of pyrrolidine and heated at 60° C. for6 h. The reaction mixture was cooled to RT, concentrated in vacuo. Theresidue was applied to a silica gel column with hexane/AcOEt (1:1) aseluent. The purified fractions were combined and concentrated in vacuoupon which the desired product crystallized out. The crystals werefiltered off and dried in a high vacuum to give 48 mg (21%) of7-methoxy-4-pyrrolidin-1-yl-quinolin-2-ylamine hydrochloride as a lightbrown solid. EI mass spectrum, m/e: 243.2 (M calculated for C₁₄H₁₇N₃O:243).

[0400] b) Above used starting material was obtained from commerciallyavailable 1-(4-chloro-7-methoxy-2-quinolyl)-3-phenylurea (500 mg, 1.53mmol) on heating in a solution of isopropanol/THF/CH₂Cl₂ (30 ml:20 ml:20ml) and in the presence of 217 mg (3 mmol) of pyrrolidine for 12 h at60° C. . Upon concentration of the reaction mixture the desired productcrystallized out. It was filtered off by suction and dried in a highvacuum to give 250 mg (78%) of the 4-chloro-7-methoxy-quinolin-2-ylamineas a light brown solid. ISP mass spectrum, m/e: 208.1 (M calculated forC₁₀H₉ClN₂O: 208).

Example 49

[0401] In analogy to example 45 a), from 4-chloro-7-methoxyquinoline(synthesis described in: J. Med. Chem., 1998, 4918) and pyrrolidinethere was obtained: 7-methoxy-4-pyrrolidin-1-yl-quinoline hydrochlorideas a yellow solid. ISP mass spectrum, m/e: 229.2 (M+1 calculated forC₁₄H₁₆N₂O: 229).

Example 50

[0402] In analogy to example 46, from7-methoxy-4-pyrrolidin-1-yl-quinoline hydrochloride and on treatmentwith BBr₃ in toluene under reflux there was obtained was obtained:4-pyrrolidin-1-yl-quinolin-7-ol as a brown solid. ISP mass spectrum,m/e: 215.3 (M+1 calculated for C₁₃H₁₄N₂O: 215).

Example 51

[0403] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 3,5-dimethoxybenzylchloride,7-(3,5-dimethoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 379.4(M+1 calculated for C₂₃H₂₆N₂O₃: 379).

Example 52

[0404] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 3,4-dimethoxybenzylchloride, whereby the product was isolated as free base;7-(3,4-dimethoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline as alight yellow solid. ISP mass spectrum) m/e: 379.4 (M+1 calculated forC₂₃H₂₆N₂O₃: 379).

Example 53

[0405] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with ethyl iodide, whereby theproduct was isolated as free base,7-ethoxy-2-methyl-4-pyrrolidin-1-yl-quinoline as a brown solid. ISP massspectrum, m/e: 257.1 (M+1 calculated for C₁₆H₂₀N₂O: 257).

Example 54

[0406] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with6-methyl-2-chloromethyl-pyridine,2-Methyl-7-(6-methyl-pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinolinehydrochloride as off-white solid. ISP mass spectrum, m/e: 334.3 (M+1calculated for C₂₁H₂₃N₃O: 334).

Example 55

[0407] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with2-methyl-3-chloromethyl-pyridine,2-methyl-7-(2-methyl-pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinolinehydrochloride as light yellow solid. ISP mass spectrum, m/e: 334.3 (M+1calculated for C₂₁H₂₃N₃O: 334).

Example 56

[0408] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with6-chloro-3-chloromethyl-pyridine,7-(6-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as white solid. ISP mass spectrum, m/e: 354.2 (M+1calculated for C₂₀H₂₀ClN₃O: 354).

Example 57

[0409] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with2-chloro-3-chloromethyl-pyridine,7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as white solid. ISP mass spectrum, m/e: 354.3 (M+1calculated for C₂₀H₂₀ClN₃O: 354).

Example 58

[0410] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with3-chloromethyl-2-fluoro-pyridine,7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as white solid. ISP mass spectrum, m/e: 338.2 (M+1calculated for C₂₀H₂₀FN₃O: 338).

Example 59

[0411] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with2-chloro-3-chloromethyl-6-methyl-pyridine,7-(2-chloro-6-methyl-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as light yellow solid. ISP mass spectrum, m/e: 368.2 (M+1calculated for C₂₁H₂₂ClN₃O: 368).

Example 60

[0412] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with3-bromomethyl-2-chloro-6-trifluoromethyl-pyridine, whereby the productwas isolated as free base,7-(2-chloro-6-trifluoromethyl-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinolineas a white solid. ISP mass spectrum, m/e: 422.2 (M+1 calculated forC₂₁H₁₉CIF₃N₃O: 422).

Example 61

[0413] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with5-chloromethyl-pyridine-2-carbonitrile,5-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-pyridine-2-carbonitrilehydrochloride as light yellow solid. ISP mass spectrum, m/e: 345.4 (M+1calculated for C₂₁H₂₀N₄O: 345).

Example 62

[0414] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with2-chloro-5-chloromethyl-thiophene,7-(5-chloro-thiophen-2-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as white solid. ISP mass spectrum, m/e: 359.2 (M+1calculated for C₁₉H₁₉ClN₂OS: 359).

Example 63

[0415] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 3-chloromethyl-thiophene,2-methyl-4-pyrrolidin-1-yl-7-(thiophen-3-ylmethoxy)-quinolinehydrochloride as white solid. ISP mass spectrum, m/e: 325.4 (M+1calculated for C₁₉H₂₀N₂OS: 325).

Example 64

[0416] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 4-bromobenzonitrile,whereby the product was isolated as free base,4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-benzonitrile as a whitesolid. ISP mass spectrum, m/e 330.5 (M+1 calculated for C₂₁H₁₉N₃O: 330).

Example 65

[0417] In analogy to example 6, on reaction of(S)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol hydrochloride,product of example 29, with 3-chloromethyl-2-fluoro-pyridinehydrochloride there was obtained: (S)4-(3-ethoxy-pyrrolidin-1-yl)-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-quinolinehydrochloride as a white solid. ISP mass spectrum, m/e: 382.4 (M+1calculated for C₂₂H₂₄FN₃O₂: 382).

Example 66

[0418] In analogy to example 6, on reaction of(S)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol hydrochloride,product of example 29, with 2-chloro-3-chloromethyl-pyridinehydrochloride there was obtained: (S)7-(2-chloro-pyridin-3-ylmethoxy)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolinehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 398.4(M+1 calculated for C₂₂H₂₄ClN₃O₂: 398).

Example 67

[0419] In analogy to example 6, on reaction of(S)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol hydrochloride,product of example 29, with 3-chloromethyl-pyridine hydrochloride therewas obtained: (S)4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-7-(pyridin-3-ylmethoxy)-quinolinehydrochloride as a light brown solid. ISP mass spectrum, m/e: 364.3 (M+1calculated for C₂₂H₂₅N₃O₂: 364).

Example 68

[0420] In analogy to example 6, on reaction of(S)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol hydrochloride,product of example 29, with 5-chloromethyl-pyridine-2-carbonitrile therewas obtained: (S)5-[4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-pyridine-2-carbonitrilehydrochloride as an off-white solid. ISP mass spectrum, m/e: 389.3 (M+1calculated for C₂₃H₂₄N₂O₂: 389).

Example 69

[0421] In analogy to example 6, on reaction of4-azepan-1-yl-2-methyl-quinolin-7-ol hydrochloride, product of example40, with 3-methoxybenzyl chloride there was obtained:4-azepan-1-yl-7-(3-methoxy-benzyloxy)-2-methyl-quinoline hydrochlorideas a light yellow solid. ISP mass spectrum, m/e: 377.4 (M+1 calculatedfor C₂₄H₂₈N₂O₂: 377).

Example 70

[0422] In analogy to example 6, on reaction of4-azepan-1-yl-2-methyl-quinolin-7-ol hydrochloride, product of example40, with 2-bromomethyl-benzonitrile there was obtained:2-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl) -benzonitrilehydrochloride as an off-white solid. ISP mass spectrum, m/e: 372.3 (M+1calculated for C₂₄H₂₅N₃O: 372).

Example 71

[0423] In analogy to example 6, on reaction of4-azepan-1-yl-2-methyl-quinolin-7-ol hydrochloride, product of example40, with 3-chlorobenzyl chloride there was obtained:4-azepan-1-yl-7-(3-chloro-benzyloxy)-2-methyl-quinoline hydrochloride asa light yellow solid. ISP mass spectrum, m/e: 381.3 (M+1 calculated forC₂₃H₂₅ClN₂O: 381).

Example 72

[0424] In analogy to example 6, on reaction of4-azepan-1-yl-2-methyl-quinolin-7-ol hydrochloride, product of example40, with 4-chlorobenzyl chloride there was obtained:4-Azepan-1-yl-7-(4-chloro-benzyloxy)-2-methyl-quinoline hydrochloride asa light yellow solid. ISP mass spectrum, m/e: 381.3 (M+1 calculated forC₂₃H₂₅ClN₂O: 381).

Example 73

[0425] A suspension of 98.5 mg (0.25 mmol) of7-(6-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride, product of example 56, in 0.44 ml (5 mmol) of morpholinewas heated under nitrogen at 60° C. (oil bath temperature) for 23 h andfurther 72 h at 100° C. The mixture was cooled to RT and partitionedbetween EtOAc and water. The organic layer was separated, washed withwater, dried over magnesium acetate and concentrated in vacuo. Theresidue was taken up in ether (20 ml), insoluble material was removed byfiltration and the filtrate treated with 0.1 ml of 3 N HCl in MeOH. Thesolid that precipitated was collected, triturated with ether (5 ml),filtered off by suction, dried in a high vacuum and then applied to a tosilica gel column with CH₂Cl₂/MeOH/NH₄OH (19:1:0.05) as eluent. Thepurified fractions were combined and concentrated in vacuo to a smallvolume then acidified by adding a few drops of 3 N HCl in MeOH. Thesolvent was taken off in vacuo to give 23 mg (18%) of the desired2-methyl-7-(6-morpholin-4-yl-pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinolinehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 405.5(M+1 calculated for C₂₄H₂₈N₄O₂: 405).

Example 74

[0426] A suspension of 98.5 mg (0.25 mmol) of7-(6-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride, product of example 56, 16 mg (0.03 mmol) of BINAP, 2.8 mg(0.01 mmol) of Pd(II) acetate, and 99 mg (1 mmol) of sodiumtert-butylate in toluene (4.5 ml) was treated at RT with 36 mg (0.5mmol) of pyrrolidine and then heated at reflux under an argon atmospherefor 4 h. The reaction mixture was cooled to RT, diluted with methylenechloride (10 ml), and then filtered. The filtrate was concentrated invacuo, the residue triturated with ether, filtered off by suction anddried in a high vacuum to give 88 mg (84%) of the2-methyl-4-pyrrolidin-1-yl-7-(6-pyrrolidin-1-yl-pyridin-3-ylmethoxy)-quinolineas a white solid. ISP mass spectrum, m/e: 389.3 (M+1 calculated forC₂₄H₂₈N₄O: 389).

Example 75

[0427] A suspension of 114 mg (0.5 mmol) of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 2, 71 mg(0.53 mmol) of 3-dimethylamino-2,2-dimethyl-1-propanol, 196.7 mg (0.75mmol) of triphenyl phosphine in THF (4 ml) was treated at RT with 123 μl(0.75 mmol) of diethyl azodicarboxylate and stirred at RT for 48 h. Theprecipitate that had formed was removed by filtration, the filtrate wasconcentrated in vacuo and the oily residue obtained was applied tosilica gel column with CH₂Cl₂/MeOH/NH₄OH (90:10:1) as eluent. Thepurified fractions were combined and concentrated in vacuo. The residuewas taken up in ether, the crystalline solid that formed was filteredoff by suction and dried in a high vacuum to give 24 mg (23%) of thedesired[2,2-dimethyl-3-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-propyl]-dimethyl-amineas an off-white solid. ISP mass spectrum, m/e: 342.4 (M+1 calculated forC₂₁H₃₁N₃O: 342). (Further material, 30 mg, 29%, was obtained onconcentration of the mother liquid and collection of the product ashydrochloride salt).

Example 76

[0428] In analogy to example 75, on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, with4-hydroxy-1-methylpiperidine there was obtained:2-methyl-7-(1-methyl-piperidin-4-yloxy)-4-pyrrolidin-1-yl-quinoline as ayellow solid. ISP mass spectrum, m/e: 326.5 (M+1 calculated forC₂₀H₂₇N₃O: 326).

Example 77

[0429] In analogy to example 75, on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, with3-hydroxy-tetrahydrofurane there was obtained:2-methyl-4-pyrrolidin-1-yl-7-(tetrahydro-furan-3-yloxy)-quinoline as alight yellow solid. ISP mass spectrum, m/e: 299.4 (M+1 calculated forC₁₈H₂₂N₂O₂: 299).

Example 78

[0430] In analogy to example 75, on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, with(1-methyl-piperidin-4-yl)-methanol, and on isolation of the product ashydrochloride, there was obtained:2-Methyl-7-(1-methyl-piperidin-4-ylmethoxy)-4-pyrrolidin-1-yl-quinolinehydrochloride as a white solid. ISP mass spectrum, m/e: 340.3 (M+1calculated for C₂₁H₂₉N₃O: 340).

Example 79

[0431] In analogy to example 75, on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, with3-morpholin-4-yl-propan-1-ol, and on isolation of the product ashydrochloride, there was obtained:2-methyl-7-(3-morpholin-4-yl-propoxy)-4-pyrrolidin-1-yl-quinolinehydrochloride as an off-white solid. ISP mass spectrum, m/e: 356.4 (M+1calculated for C₂₁H₂₉N₃O₂: 356).

Example 80

[0432] To a cooled (0° C.) solution of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol (797 mg, 3.49 mmol) indimethylformamide (13 mL) was added sodium hydride (ca. 60% in oil, 168mg, 4.19 mmol). After 30 min at 0° C., ethyl bromoacetate (0.5 mL, 4.50mmol) was injected. After 2 h30, an aqueous solution of NaHCO₃ was addedand the aqueous layer was extracted with dichloromethane. The combinedorganic phases were washed with brine and water and then dried oversodium sulfate. After filtration, solvents were removed in a highvacuum. The brown oil was triturated with diethylether. Afterfiltration, the solid was dried in a high vacuum to give 660 g (60.2%)of (2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-acetic acid ethyl esteras a light brown solid. ISP mass spectrum, m/e: 315.4 (M+1 calculatedfor C₁₈H₂₂N₂O₃: 315.4).

Example 81

[0433] To a cooled (0° C.) solution of(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-acetic acid ethyl ester(613 mg, 1.95 mmol) in ethyl alcohol (10 mL) was added sodiumborohydride (506 mg, 12.84 mmol). The mixture was stirred 7 h at roomtemperature. Aqueous hydrochloride was added carefully (12M, 1 mL). Thesuspension was filtered and the solid was washed with MeOH. The solutionwas dried over sodium sulfate, filtered and the solvent was removed in ahigh vacuum to give 425 mg (80.0%) of2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-ethanol as a brown oil.ISP mass spectrum, m/e: 273.4 (M+1 calculated for C₁₆H₂₀N₂O₂: 273.4).

Example 82

[0434] To a cooled (0° C.) solution of of2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-ethanol (425 mg, 1.56mmol) in dichloromethane (20 mL) was added triethylamine (0.9 mL, 6.49mmol) and tosyl chloride (1115 mg, 5.85 mmol). The reaction mixture wasstirred 22 h at room temperature. An aqueous solution of NaHCO3 wasadded. After separation, the organic layer was washed with brine. Thebrown gum was triturated with diethylether. After filtration, the solidwas dried in a high vacuum to give 520 mg (78.1%) of toluene-4-sulfonicacid 2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-ethyl ester as alight yellow solid. ISP mass spectrum, m/e: 427.5 (M+1 calculated forC₂₃H₂₆N₂O₄S: 427.5).

Example 83

[0435] In analogy to example 6 there was prepared: on reaction of2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with1-(2-pyridyl)-3-chloropropane, there was obtained:2-methyl-7-(3-pyridin-2-yl-propoxy)-4-pyrrolidin-1-yl-quinoline as ayellow viscous oil. ISP mass spectrum, m/e348.5 (M+1 calculated forC₂₂H₂₅N₃O: 348.5).

Example 84

[0436] In analogy to example 1, on reaction of7-benzyloxy-4-chloro-2-methyl-quinoline with morpholine, there wasobtained: 7-benzyloxy-2-methyl-4-morpholin-4-yl-quinoline as a waxyyellow solid. ISP mass spectrum, m/e: 335.3 (M+1 calculated forC₂₁H₂₂N₂O₂: 335).

Example 85

[0437] In analogy to example 1, on reaction of7-benzyloxy-4-chloro-2-methyl-quinoline, with an excess of(S)-3-hydroxypyrrolidine (2,5 mole-equivalents) in1-methyl-2-pyrrolidone as solvent at 100° C., there was obtained:(S)-1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-3-ol as a lightbrown solid. ISP mass spectrum, m/e: 335.4 (M+1 calculated forC₂₁H₂₂N₂O₂: 335).

Example 86

[0438] In analogy to example 1, on reaction of7-benzyloxy-4-chloro-2-methyl-quinoline, with an excess of(R)-3-hydroxypyrrolidine (2,5 mole-equivalents) in1-methyl-2-pyrrolidone as solvent at 100° C., there was obtained:(R)-1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-3-ol as a lightbrown solid. ISP mass spectrum, m/e: 335.3 (M+1 calculated forC₂₁H₂₂N₂O₂: 335).

Example 87

[0439] In analogy to example 1, on reaction of7-benzyloxy-4-chloro-2-methyl-quinoline, with an excess of(S)-2-(hydroxymethyl)pyrrolidine (2,5 mole-equivalents) in1-methyl-2-pyrrolidone as solvent at 100° C., there was obtained:(S)-[1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-2-yl]-methanol asan off-white solid. ISP mass spectrum, m/e: 349.5 (M+1 calculated forC₂₂H₂₄N₂O₂: 349).

Example 88

[0440] In analogy to example 1, on reaction of7-benzyloxy-4-chloro-2-methyl-quinoline, with an excess of(S)-2-(methoxymethyl)pyrrolidine (2,5 mole-equivalents) in1-methyl-2-pyrrolidone as solvent at 100° C., there was obtained:(S)-7-benzyloxy-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolineas an orange viscous oil. ISP mass spectrum, m/e: 363.2 (M+1 calculatedfor C₂₃H₂₆N₂O₂: 363).

Example 89

[0441] In analogy to example 2, on hydrogenation of(S)-7-benzyloxy-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinoline,product of example 88, with Pd on charcoal (10%) in MeOH, there wasobtained: (S)-4-(2-Methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-olas a yellow solid. ISP mass spectrum, m/e: 273.2 (M+1 calculated forC₁₆H₂₀N₂O₂: 273).

Example 90

[0442] In analogy to example 6, on reaction of(S)-4-(2-Methoxymethyl-pyrrolidin-1-yl)-2 methyl-quinolin-7-ol, productof example 89, with 2-chloro-3-chloromethyl-pyridine hydrochloride therewas obtained:(S)-7-(2-chloro-pyridin-3-ylmethoxy)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolinehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 398.4(M+1 calculated for C₂₂H₂₄ClN₃O₂: 398).

Example 91

[0443] In analogy to example 6, on reaction of(S)-4-(2-Methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol, productof example 89, with 2-fluoro-3-chloromethyl-pyridine hydrochloride therewas obtained:(S)-7-(2-fluoro-pyridin-3-ylmethoxy)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolinehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 382.4(M+1 calculated for C₂₂H₂₄FN₃O₂: 382).

Example 92

[0444] In analogy to example 6, on reaction of(S)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol, productof example 89, with cyclopropylmethyl bromide hydrochloride there wasobtained:(S)-7-cyclopropylmethoxy-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolinehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 327.4(M+1 calculated for C₂₂H₂₆N₂O₂: 327).

Example 93

[0445] In analogy to example 2, on hydrogenation of(S)-[1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-2-yl]-methanol,product of example 87, with Pd on charcoal (10%) in MeOH, there wasobtained: (S)-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-olas a yellow solid. ISP mass spectrum, m/e: 259.3 (M+1 calculated forC₁₅H₁₈N₂O₂: 259).

Example 94

[0446] In analogy to example 6, on reaction of(S)-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol, productof example 93, with 2-fluoro-3-chloromethyl-pyridine hydrochloride therewas obtained:(S)-{1-[7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-quinolin-4-yl]-pyrrolidin-2-yl}-methanolas a light yellow solid. ISP mass spectrum, m/e: 368.4 (M+1 calculatedfor C₂₁H₂₂FN₃O₂: 368).

Example 95

[0447] In analogy to example 6, on reaction of(S)-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol, productof example 93, with 2-chloro-3-chloromethyl-pyridine hydrochloride therewas obtained:(S)-{1-[7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-quinolin-4-yl]-pyrrolidin-2-yl}-methanolas a light yellow solid. ISP mass spectrum, m/e: 384.3 M+1 calculatedfor C₂₁H₂₂ClN₃O₂: 384).

Example 96

[0448] In analogy to example 6, on reaction of(S)-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol, productof example 93, with 2-bromomethyl-benzonitrile there was obtained:(S)-2-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileas an off-white solid. ISP mass spectrum, m/e: 374.5 (M+1 calculated forC₂₃H₂₃N₃O₂: 374).

Example 97

[0449] In analogy to example 6, on reaction of(S)-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol, productof example 93, with 3-chlormethyl-pyridine there was obtained:(S)-{1-[2-methyl-7-(pyridin-3-ylmethoxy)-quinolin-4-yl]-pyrrolidin-2-yl}-methanolas an light yellow solid. ISP mass spectrum, m/e: 350.5 (M+1 calculatedfor C₂₁H₂₃N₃O₂: 350).

Example 98

[0450] In analogy to example 6, on reaction of(S)-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol, productof example 93, with 5-chloromethyl-pyridin-2-carbonitrile there wasobtained:(S)-5-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-pyridine-2-carbonitrileas an light yellow solid. ISP mass spectrum, m/e: 375.3 (M+1 calculatedfor C₂₂H₂₂N₄O₂: 375).

Example 99

[0451] a) A mixture of 3.1 g of (10.9 mmol) of7-benzyloxy-4-chloro-6-fluoro-2-methyl-quinoline and 18.1 ml (21.8 mmol)pyrrolidine was heated at 80° C. (oil bath temperature) under an argonatmosphere for 6 h. The reaction mixture was concentrated in vacuo, theresidue taken up in methylene chloride, which was washed with water,saturated NaCl solution and then dried over magnesium sulphate. Thesolvent was removed in vacuo, the residue purified by flashchromatography on silica gel with CH₂Cl₂/MeOH (100:0 to 90:10 over 1 h)as eluent. Combination of the purified fractions and concentration invacuo gave 1.7 g (46.2%) of the7-benzyloxy-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinoline as a browncrystalline solid. ISP mass spectrum, m/e: 337.4 (M+1 calculated forC₂₁H₂₁FN₂O: 337).

[0452] Preparation of the Starting Material:

[0453] b) A solution of 50 g (0.354 mol) of 4-fluoro-3-methoxy-anilinedissolved in methylene chloride (1800 ml) was treated under argon with163.2 g (0.44 mol) of tetrabutyl-ammonium iodide, cooled to −75° C. andthe treated over a period of 25 minutes with 860 ml of 1 M BCl₃ inmethylene chloride while keeping the reaction solution between −75° C.and −64° C. The solution was stirred for 15 minutes the cooling bath wasremoved and stirring was continued for 24 h under argon. The reactionsolution was poured into ice water (6 l) with stirring, the layers wereseparated, the water layer twice extracted with methylene chloride (each1.5 l). The combined organic layers were washed twice with water (each 2l) and discarded. The combined aqueous layers were made basic with solidNaHCO₃, saturated with NaCl, extracted 3 times with 2.5 l of ether andtwice with 1.5 l of AcOEt. The combined organic layers were tried overmagnesium sulphate and concentrated in vacuo to give 43.9 g (87.8%) of4-fluoro-3-hydroxy-aniline as light brown crystalline solid. Meltingpoint: 156-157° C.

[0454] c) 79 g (0.62 mol) of 4-fluoro-3-hydroxy-aniline in DMF (1.3 l)were treated under argon portion wise over a period of 15 minutes with76.7 g (0.68 mol) of potassium t-butylate whereas the temperature of thereaction solution was kept between RT and 28° C. Stirring was continuedfor 15 minutes then 79 ml (0.68 mol) of benzyl chloride were addeddropwise while keeping the temperature of the reaction solution betweenRT and 30° C. After stirring for 2 h at RT the reaction solution waspoured into ice water (6 l) which was then extracted 3-fold with ether(about 3 l each). The combined organic layers were washed with brine(1.5 l) and dried over magnesium sulfate and the solvent removed invacuo. The residue was purified by chromatography over a short silicagel column with methylene chloride as eluent. Combination of thepurified fractions and concentration in vacuo gave 92.7 g (68.6%) of thedesired 3-benzyloxy-4-fluoro-phenylamine as light yellow crystallinesolid. ISP mass spectrum, m/e: 218.2 (M+1 calculated for C₁₃H₁₂FNO:218.2).

[0455] d) 92.7 g (0.43 mol) of 3-Benzyloxy-4-fluoro-phenylamine, 57 ml(0.45 mol) of ethyl acetoacetate and 0.81 g (4 mmol) ofp-toluenesulfonic acid monohydrate in 370 ml of cyclohexane were heatedat reflux for 3 h in the presence of a water separator funnel. Thereaction mixture was cooled to RT, ACOEt (1 l) and saturated aqueousNaHCO₃ solution (0.5 l) were added, the layers were separated and theorganic layer once extracted with AcOEt (0.3 l). The combined organiclayers were dried over magnesium sulfate and concentrated in vacuo togive 140 g (100%) of the desired3-(3-benzyloxy-4-fluoro-phenylamino)-but-2-enoic acid ethyl ester asyellow-orange crystalline solid. Melting point: 79° C.-80° C.

[0456] e) 70.35 g (0.21 mol) of3-(3-benzyloxy-4-fluoro-phenylamino)-but-2-enoic acid ethyl ester inDowtherm A (220 ml) were added dropwise under argon to 400 ml ofDowtherm A heated at 250° C. (metal bath temperature). The solution wasstirred further 15 minutes at 250° C. (bath temperature), cooled to RTand n-hexane was added with stirring whereby a light brown solid formedthat was collected by filtration and washed with 4-times with n-hexane.The solid was then triturated with ether, collected by suction, washed3-times with ether and then dried in a high vacuum, to give 33.9 g (57%)of the desired7-benzyloxy-6-fluoro-2-methyl-1H-quinolin-4-one as a lightbrown solid. ISP mass spectrum, m/e: 284.1 (M+1 calculated forC₁₇H₁₄FNO₂: 284).

[0457] f) 67.8 g (0.239 mol) of7-benzyloxy-6-fluoro-2-methyl-1H-quinolin-4-one in 220 ml (2.39 mol) ofPOCl₃ were heated at reflux for 90 minutes. The reaction mixture wascooled to RT and the solvent was removed in vacuo. The residue waspartitioned between ice water (1.5 l) and methylene chloride (1 l), and250 ml of concentrated ammonia were added slowly with stirring to adjustthe aqueous layer to pH 9. The layers were separated, the aqueous layertwice extracted with methylene chloride (each 500 ml), the combinedorganic layers were washed with brine, dried over magnesium sulfate andthen concentrated in vacuo, to give 71.5 g (86.83%) of the desired of7-benzyloxy-4-chloro-6-fluoro-2-methyl-quinoline as an off white solid.Melting point: 110° C.-111° C.

Example 100

[0458] A solution of 1.5 g (4.46 mmol) of7-benzyloxy-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinoline, product ofexample 99, dissolved in 40 ml of MeOH was treated with 0.375 g ofpalladium on charcoal (10%) and then hydrogenated at RT for 1.5 h untilHPLC analysis indicated the completion of the reaction. The catalyst wasfiltered off, and the solution was concentrated in vacuo. The residuewas triturated with AcOEt, collected by filtration and dried in a highvacuum to give 1.02 g (92.8%)6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol as an yellow solid.ISP mass spectrum, m/e: 247.3 (M+1 calculated for C₁₄H₁₅FN₂O: 247).

Example 101

[0459] In analogy to example 6 there was prepared: on reaction of6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example100, with 4-bromomethyl benzonitrile whereby the product was isolated asfree base,4-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrileas an off-white solid. ISP mass spectrum, m/e: 362.2 (M+1 calculated forC₂₂H₂₀FN₃O: 362).

Example 102

[0460] In analogy to example 6 there was prepared: on reaction of6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example100, with 3-bromomethyl pyridine hydrochloride whereby the product wasisolated as free base,6-fuoro-2-methyl-7-(pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinoline asan brown solid. ISP mass spectrum, m/e: 338.2(M+1 calculated forC₂₀H₂₀FN₃O: 338).

Example 103

[0461] In analogy to example 6 there was prepared: on reaction of6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example100, with 3-chloromethyl 2-fluoro-pyridine hydrochloride whereby theproduct was isolated as free base,6-fluoro-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinolineas an brown solid. ISP mass spectrum, m/e: 356.4 (M+1 calculated forC₂₀H₁₉F₂N₃O: 356).

Example 104

[0462] In analogy to example 6 there was prepared: on reaction of6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example100, with 2-chloro-3-chloromethyl-pyridine hydrochloride whereby theproduct was isolated as free base,7-(2-chloro-pyridin-3-ylmethoxy)-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolineas a light brown solid. ISP mass spectrum, m/e: 372.3 (M+1 calculatedfor C₂₀H₁₉ClFN₃O: 372).

Example 105

[0463] In analogy to example 6 there was prepared: on reaction of6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example100, with 3-chloromethyl-2-methyl-pyridine hydrochloride whereby theproduct was isolated as free base,6-fluoro-2-methyl-7-(2-methyl-pyridin-3-ylmethoxy)-4-pyrrolidin-1-yl-quinolinean light yellow solid. ISP mass spectrum, m/e: 352.4(M+1 calculated forC₂₁H₂₂FN₃O: 352).

Example 106

[0464] In analogy to example 6 there was prepared: on reaction of6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example100, with 3-chloromethyl benzonitrile whereby the product was isolatedas free base,3-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrileas an off-white solid. ISP mass spectrum, m/e: 362.2(M+1 calculated forC₂₂H₂₀FN₃O: 362).

Example 107

[0465] In analogy to example 6 there was prepared: on reaction of6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example100, with 2-bromomethyl benzonitrile whereby the product was isolated asfree base,2-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrileas light brown solid. ISP mass spectrum, m/e: 362.2(M+1 calculated forC₂₂H₂₀FN₃O: 362).

Example 108

[0466] In analogy to example 6 there was prepared: on reaction of6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example100, with cyclopropylmethyl bromide,7-cyclopropylmethoxy-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolinehydrochloride as a yellow solid. ISP mass spectrum, m/e: 301.3(M+1calculated for C₁₈H₂₁FN₂O: 301).

Example 109

[0467] In analogy to example 6 there was prepared: on reaction of6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example100, with 5-chloromethyl-pyridine-2-carbonitrile, whereby the productwas isolated as free base,5-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-pyridine-2-carbonitrileas light grey solid. ISP mass spectrum, m/e: 363.2(M+1 calculated forC₂₁H₁₉FN₄O: 363).

Example 110

[0468] A suspension of 3.2 g (9.5 mmol) of(R)-1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-3-ol, product ofexample 86, in THF (275 ml) was treated at RT under nitrogen with 1.42 g(12.4 mmol) of potassium tert-butoxide. The suspension was stirred for20 minutes at RT then 0.72 ml (11.4 mmol) of methyl iodide were added.After 25 minutes of stirring further 0.284 g (2.48 mmol) of potassiumtert-butoxide were added followed by 0.144 ml (2.28 mol) of methyliodide (10 minutes later) for completion of the reaction. Stirring wascontinued for 20 minutes, the reaction mixture was then concentrated invacuo and the residue partitioned between water and AcOEt. The layerswere separated the aqueous layer once extracted with AcOEt, the combinedorganic layers washed with brine, dried over magnesium sulphate andconcentrated in vacuo to give 3.33 g (94.5%)(R)-7-benzyloxy-4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinoline as anorange viscous oil. ISP mass spectrum, m/e: 349.5 (M+1 calculated forC₂₂H₂₄FN₂O2: 349).

Example 111

[0469] In analogy to example 110 there was prepared: on reaction of(S)-1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-3-ol, product ofexample 85, with 2-bromoethyl methyl ether,(S)-7-benzyloxy-4-[3-(2-methoxy-ethoxy)-pyrrolidin-1-yl]-2-methyl-quinoline an orange viscous oil. ISP massspectrum, m/e: 393.4 (M+1 calculated for C₂₄H₂₈N₂O₃: 393).

Example 112

[0470] In analogy to example 110 there was prepared: on reactionof(S)-1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-3-ol, product ofexample 85, with methyl iodide,(S)-7-benzyloxy-4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinoline as anyellow viscous oil. ISP mass spectrum, m/e: 349.3 (M+1 calculated forC₂₂H₂₄N₂O₂: 349).

Example 113

[0471] In analogy to example 110 there was prepared: on reaction of(S)-1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-3-ol, product ofexample 85, with cyclopropyl bromide,(S)-7-benzyloxy-4-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-2-methyl-quinolineas an orange viscous oil. ISP mass spectrum, m/e: 389.2 (M+1 calculatedfor C₂₅H₂₈N₂O₂: 389).

Example 114

[0472] In analogy to example 110 there was prepared: on reaction of(S)-1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-3-ol, product ofexample 85, with toluene-4-sulfonic acid 3-methoxy-propyl ester,(S)-7-benzyloxy-4-[3-(3-methoxy-propoxy)-pyrrolidin-1-yl]-2-methyl-quinolineas an yellow viscous oil. ISP mass spectrum, m/e: 407.3 (M+1 calculatedfor C₂₅H₃₀N₂O₃: 407).

Example 115

[0473] In analogy to example 110 there was prepared: on reaction of(S)-1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-3-ol, product ofexample 85, with 2-(2-bromo-ethoxy)-tetrahydro-pyran,7-benzyloxy-2-methyl-4-{(3S)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-pyrrolidin-1-yl}-quinolineas an yellow viscous oil. ISP mass spectrum, m/e: 363.4 (M+1 calculatedfor C₂₈H₃₄N₂O₄: 463).

Example 116

[0474] In analogy to example 2, on hydrogenation of(S)-7-benzyloxy-4-[3-(2-methoxy-ethoxy)-pyrrolidin-1-yl]-2-methyl-quinoline,product of example 111, with Pd on charcoal (10%) in MeOH, there wasobtained:(S)-4-[3-(2-methoxy-ethoxy)-pyrrolidin-1-yl]-2-methyl-quinolin-7-ol as ayellow solid. ISP mass spectrum, m/e: 303.4 (M+1 calculated forC₁₇H₂₂N₂O₃: 303).

Example 117

[0475] In analogy to example 2, on hydrogenation of(S)-7-benzyloxy-4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinoline,product of example 112, with Pd on charcoal (10%) in MeOH, there wasobtained: (S)-4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol as ayellow solid. ISP mass spectrum, m/e: 259.2 (M+1 calculated forC₁₅H₁₈N₂O₂: 259).

Example 118

[0476] In analogy to example 2, on hydrogenation of(S)-7-benzyloxy-4-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-2-methyl-quinoline,product of example 113, with Pd on charcoal (10%) in MeOH, there wasobtained:(S)-4-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol as ayellow solid. ISP mass spectrum, m/e: 299.3 (M+1 calculated forC₁₈H₂₂N₂O₂: 299).

Example 119

[0477] In analogy to example 2, on hydrogenation of(S)-7-benzyloxy-4-[3-(3-methoxy-propoxy)-pyrrolidin-1-yl]-2-methyl-quinoline,product of example 114, with Pd on charcoal (10%) in MeOH, there wasobtained:(S)-4-[3-(3-methoxy-propoxy)-pyrrolidin-1-yl]-2-methyl-quinolin-7-ol asa yellow solid. ISP mass spectrum, m/e: 317 (M+1 calculated forC₁₈H₂₄N₂O₃: 317).

Example 120

[0478] In analogy to example 2, on hydrogenation of7-benzyloxy-2-methyl-4-{(3S)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-pyrrolidin-1-yl}-quinoline, product of example 115, with Pd oncharcoal (10%) in MeOH, there was obtained:2-methyl-4-{(3S)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-pyrrolidin-1-yl}-quinolin-7-olas a yellow solid. ISP mass spectrum, m/e: 373.4.3 (M+1 calculated forC₂₁H₂₈N₂O₄: 373).

Example 121

[0479] In analogy to example 6, on reaction of(S)-4-[3-(2-methoxy-ethoxy)-pyrrolidin-1-yl]-2-methyl-quinolin-7-ol,product of example 116, with 4-bromomethyl benzonitrile there wasobtained:(S)-4-{4-[3-(2-methoxy-ethoxy)-pyrrolidin-1-yl]-2-methyl-quinolin-7-yloxymethyl}-benzonitrilehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 418.4(M+1 calculated for C₂₅H₂₇N₃O₃: 418.4).

Example 122

[0480] In analogy to example 6, on reaction of(S)-4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol, product ofexample 117, with 4-bromomethyl benzonitrile there was obtained:(S)-4-[4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrilehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 374.4(M+1 calculated for C₂₃H₂₃N₃O₂: 374).

Example 123

[0481] In analogy to example 6, on reaction of(S)-4-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol,product of example 118, with 4-bromomethyl benzonitrile there wasobtained:(S)-4-[4-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrilehydrochloride as an off-white solid. ISP mass spectrum, m/e: 414.4 (M+1calculated for C₂₆H₂₇N₃O₂: 414).

Example 124

[0482] In analogy to example 6, on reaction of(S)-4-[3-(3-methoxy-propoxy)-pyrrolidin-1-yl]-2-methyl-quinolin-7-ol,product of example 119, with 4-bromomethyl benzonitrile there wasobtained:(S)-4-{4-[3-(3-methoxy-propoxy)-pyrrolidin-1-yl]-2-methyl-quinolin-7-yloxymethyl}-benzonitrilehydrochloride as an off-white solid. ISP mass spectrum, m/e: 432.5 (M+1calculated for C₂₆H₂₉N₃O₃: 432).

Example 125

[0483] In analogy to example 6, on reaction of2-methyl-4-{(3S)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-pyrrolidin-1-yl}-quinolin-7-ol,product of example 120, with 4-bromomethyl benzonitrile, and subsequentcleavage of the THP ether protecting group whereby the product wasisolated as free base, there was obtained:(S)-4-{4-[3-(2-Hydroxy-ethoxy)-pyrrolidin-1-yl]-2-methyl-quinolin-7-yloxymethyl}-benzonitrileas a white yellow solid. ISP mass spectrum, m/e: 405.3 (M+1 calculatedfor C₂₄H₂₅N₃O₃: 403).

Example 126

[0484] In analogy to example 99, on reaction of7-benzyloxy-4-chloro-6-fluoro-2-methyl-quinoline, with an excess of(S)-2-(hydroxymethyl)pyrrolidine (2,5 mole-equivalents) in1-methyl-2-pyrrolidone as solvent at 100° C., there was obtained:(S)-[1-(7-benzyloxy-6-fluoro-2-methyl-quinolin-4-yl)-pyrrolidin-2-yl]-methanolas an light brown solid. ISP mass spectrum, m/e: 367.3 (M+1 calculatedfor C₂₂H₂₃FN₂O₂: 367).

Example 127

[0485] In analogy to example 100, on hydrogenation of(S)-[1-(7-benzyloxy-6-fluoro-2-methyl-quinolin-4-yl)-pyrrolidin-2-yl]-methanol,product of example 126, with Pd on charcoal (10%) in MeOH, there wasobtained:(S)-6-fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-olas a light brown solid. ISP mass spectrum, m/e: 277.3 (M+1 calculatedfor C₁₅H₁₇FN₂O₂: 277).

Example 128

[0486] In analogy to example 6, on reaction of(S)-6-fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol,product of example 127, with 4-bromomethyl benzonitrile, whereby theproduct was isolated as free base, there was obtained:(S)-4-[6-fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileas an light grey solid. ISP mass spectrum, m/e: 392.3 (M+1 calculatedfor C₂₃H₂₂FN₃O₂: 392).

Example 129

[0487] In analogy to example 6, on reaction of(S)-6-fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-ol,product of example 127, with 5-chloromethyl-pyridine-2-carbonitrile,whereby the product was isolated as free base, there was obtained:(S)-5-[6-fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-pyridine-2-carbonitrileas a grey solid. ISP mass spectrum, m/e: 393.3 (M+1 calculated forC₂₂H₂₁FN₄O₂: 393).

Example 130

[0488] a) A solution of 1.42 g of (4.6 mmol) of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile and 1.11 g(12.5 mmol) of (S)-3-hydroxypyrrolidine in 1-methyl-2-pyrrolidine (25ml) was heated under nitrogen at 100° C. (oil bath temperature) for 23h. The reaction mixture was concentrated in a high vacuum, the residuetaken up in methylene chloride, which was washed with water, saturatedNaCl solution and then dried over magnesium sulphate. The solvent wasremoved in vacuo, the residue triturated with MeOH, filtered off bysuction, washed subsequently with MeOH and ether and then dried in ahigh vaccum to give 1.45 g (83.86%) of the(S)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileas a brown solid. ISP mass spectrum, m/e: 360.2 (M+1 calculated forC₂₂H₂₁N₃O₂: 360.2).

[0489] Preparation of the Starting Material:

[0490] b) A solution of 3 g (10.5 mmol) of7-benzyloxy-2-methyl-quinolin-4-ol, product of example 1 c), dissolvedin 270 ml of MeOH was treated with 1 g of palladium on charcoal (10%)and then hydrogenated at RT for 1 h until HPLC analysis indicated thecompletion of the reaction. The catalyst was filtered off, washed withMeOH, and the solution was concentrated in vacuo. The residue wastriturated with ether, collected by filtration and dried in a highvacuum to give 2.05 g (98.6%) 2-methyl-quinoline-4,7-diol as anoff-white solid. ISP mass spectrum, m/e: 176.2 (M+1 calculated forC₁₀H₉NO₂: 176).

[0491] c) A mixture of 2.05 g (10.4 mmol) of2-methyl-quinoline-4,7-diol, 1.72 g (12.5 mmol) of potassium carbonateand 2.1 g (12.5 mmol) of 4-(bromomethyl)-benzonitrile in 100 ml of DMFwere stirred at RT under an nitrogen atmosphere for 4 h until completionof the reaction according to HPLC analysis. The reaction mixture wascooled to RT and poured into EtOAc/water (300 ml/400 ml). The productthat precipitated was filtered off by suction, washed with water, AcOEtand ether and dried in a high vacuum to give 2.23 g (73%) of4-(4-hydroxy-2-methyl-quinolin-7-yloxymethyl)-benzonitrile as a whitesolid. ISP mass spectrum, m/e: 291.4 (M+1 calculated for C₁₈H₁₄N₂O₂:291).

[0492] d) 2.22 g (7.6 mmol) of4-(4-hydroxy-2-methyl-quinolin-7-yloxymethyl)-benzonitrile in 14.2 ml(151.7 mmol) of POCl₃ were heated at 130° C. (oil bath temperature) for1 h 50 min until completion of the reaction according to TLC analysis.The reaction mixture was cooled to RT and the solvent was removed invacuo. The residue was taken up in ice water and stirred for 15 minutes.The pH was adjusted to values between pH 9-10 with concentrated NH₄OH anstirring was continued for 2 h. The brown solid, which precipitated wasfiltered off by suction, washed with water and subsequently dried in ahigh vacuum. This gave 2.38 g (100%) of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile as a yellowsolid. ISP mass spectrum, m/e: 209 (M+1 calculated for C₁₈H₁₃ClN2O:309).

Example 131

[0493] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R)-3-hydroxypyrrolidine, there was obtained:(R)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileas a brown solid. ISP mass spectrum, m/e: 360.3 (M+1 calculated forC₂₁H₂₁N₃O₂: 360).

Example 132

[0494] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R,S)-2-methylpyrrolidine, there was obtained:(R,S)-4-[2-methyl-4-(2-methyl-pyrrolidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrileas a beige solid. ISP mass spectrum, m/e: 358.2 (M+1 calculated forC₂₃H₂₃N₃O: 358).

Example 133

[0495] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (S)-2-(hydroxymethyl)pyrrolidine, there wasobtained:(S)-4-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileas a light yellow solid. ISP mass spectrum, m/e: 374.4 (M+1 calculatedfor C₂₃H₂₃N₃O2: 374).

Example 134

[0496] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R)-2-(hydroxymethyl)pyrrolidine, there wasobtained:(R)-4-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileas a light yellow solid. ISP mass spectrum, m/e: 374.4 (M+1 calculatedfor C₂₃H₂₃N₃O₂: 374).

Example 135

[0497] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R)-3-(dimethylamino)pyrrolidine, there wasobtained:(R)-4-[4-(3-dimethylamino-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileas a light brown solid. ISP mass spectrum, m/e: 387.3 (M+1 calculatedfor C₂₄H₂₆N₄O: 387).

Example 136

[0498] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (S)-3-(dimethylamino)pyrrolidine, there wasobtained:(S)-4-[4-(3-dimethylamino-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileas a light brown solid. ISP mass spectrum, m/e: 387.3 (M+1 calculatedfor C₂₄H₂₆N₄O: 387).

Example 137

[0499] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R)-2-(methoxymethyl)pyrrolidine, there wasobtained:(R)-4-[4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileas a light brown solid. ISP mass spectrum, m/e: 388.3 (M+1 calculatedfor C₂₄H₂₅N₃O₂: 388).

Example 138

[0500] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (S)-2-(methoxymethyl)pyrrolidine, there wasobtained:(S)-4-[4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileas a light brown solid. ISP mass spectrum, m/e: 388.3 (M+1 calculatedfor C₂₄H₂₅N₃O₂: 388).

Example 139

[0501] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R,S)-2-isopropyl-pyrrolidine, there was obtained:(R,S)-4-[4-(2-isopropyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrilehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 386.4(M+1 calculated for C₂₅H₂₇N₃O: 386).

Example 140

[0502] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (S)-proline methyl ester, there was obtained:(S)-1-[7-(4-cyano-benzyloxy)-2-methyl-quinolin-4-yl]-pyrrolidine-2-carboxylicacid methyl ester as a white solid. ISP mass spectrum, m/e: 402.5 (M+1calculated for C₂₄H₂₃N₃O₃: 402).

Example 141

[0503] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R)-3-(methylamino)pyrrolidine there was obtained:(R)-4-[2-methyl-4-(3-methylamino-pyrrolidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrileas a yellow foam. ISP mass spectrum, m/e: 373.4 (M+1 calculated forC₂₃H₂₄N₄O: 373).

Example 142

[0504] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (S)-3-(methylamino)pyrrolidine there was obtained:(S)-4-[2-methyl-4-(3-methylamino-pyrrolidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrileas a brown foam. ISP mass spectrum, m/e: 373.4 (M+1 calculated forC₂₃H₂₄N₄O: 373).

Example 143

[0505] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with piperidine there was obtained:4-(2-methyl-4-piperidin-1-yl-quinolin-7-yloxymethyl)-benzonitrilehydrochloride as a yellow solid. ISP mass spectrum, m/e: 358.3 (M+1calculated for C₂₃H₂₃N₃O: 358).

Example 144

[0506] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with morpholine there was obtained:4-(2-methyl-4-morpholin-4-yl-quinolin-7-yloxymethyl) -benzonitrilehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 360.3(M+1 calculated for C₂₂H₂₁N₃O₂: 360).

Example 145

[0507] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R,S)-3-(diethylamino)pyrrolidine there wasobtained:(R,S)-4-[4-(3-diethylamino-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrilehydrochloride as a light brown solid. ISP mass spectrum, m/e: 415.4 (M+1calculated for C₂₂H₂₁N₃O₂: 415).

Example 146

[0508] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R,S)-2-(pyrrolidin-3yl)-pyridine there wasobtained:(R,S)-4-[2-methyl-4-(3-pyridin-2-yl-pyrrolidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrilehydrochloride as a brown solid. ISP mass spectrum, m/e: 421.4 (M+1calculated for C₂₇H₂₄N₄O: 421).

Example 147

[0509] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R,S)-4-(pyrrolidin-3-yl)-pyridine there wasobtained:(R,S)-4-[2-methyl-4-(3-pyridin-4-yl-pyrrolidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrileas a white solid. ISP mass spectrum, m/e: 421.4 (M+1 calculated forC₂₇H₂₄N₄O: 421).

Example 148

[0510] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (S)-1-(2-pyrrolidinylmethyl)pyrrolidine there wasobtained:(S)-4-[2-methyl-4-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrilehydrochloride as a brown solid. ISP mass spectrum, m/e: 427.6 (M+1calculated for C₂₇H₃₀N₄O: 427).

Example 149

[0511] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R,S)-3-(methylsulfonyl)-pyrrolidine there wasobtained:(R,S)-4-[4-(3-methanesulfonyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrilehydrochloride as a light brown solid. ISP mass spectrum, m/e: 422.4 (M+1calculated for C₂₃H₂₃N₃O₃S: 422).

Example 150

[0512] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R,S)-3-methyl-piperidine there was obtained:(R,S)-4-[2-methyl-4-(3-methyl-piperidin-1-yl)-quinolin-7-yloxymethyl]-benzonitrilehydrochloride as a light yellow solid. ISP mass spectrum, m/e: 372.4(M+1 calculated for C₂₄H₂₅N₃O: 372).

Example 151

[0513] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with 1,4-dioxa-8-azaspiro{4.5}decane there was obtained:4-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileas a light yellow solid. ISP mass spectrum, m/e: 416.4 (M+1 calculatedfor C₂₅H₂₅N₃O₃: 416).

Example 152

[0514] In analogy to example 130, on reaction of4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile, product ofexample 130 d), with (R,S)-3-(hydroxymethyl)piperidine there wasobtained:(R,S)-4-[4-(3-hydroxymethyl-piperidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileas a light yellow solid. ISP mass spectrum, m/e: 388.3 (M+1 calculatedfor C₂₄H₂₅N₃O₂: 388).

Example A

[0515] A compound of formula I can be used in a manner known per se asthe active ingredient for the production of tablets of the followingcomposition: Per tablet Active ingredient 200 mg Microcrystallinecellulose 155 mg Corn starch 25 mg Talc 25 mgHydroxypropylmethylcellulose 20 mg 425 mg

Example B

[0516] A compound of formula I can be used in a manner known per se asthe active ingredient for the production of capsules of the followingcomposition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mgLactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

[0517] Upon reading the present specification various embodiments willbecome obvious to the skilled artisan. These variations are to beconsidered within the scope and spirit of the present invention which isonly to be limited by the claims that follow and their equivalents.

What is claimed is:
 1. A compound of formula:

wherein: R¹ is hydrogen, alkyl, alkoxyalkyl, alkenyl, alkinyl,hydroxyalkyl, aralkyl, heterocyclylalkyl, cycloalkylalkyl, NH₂—SO₂—,monoalkylamino-SO₂—, dialkylamino-SO₂—, alkyl-SO₂—, aryl, NH₂-alkyl,monoalkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylalkyl,carboxyalkyl, aryl-SO₂—O-alkyl, cycloalkyl, or cycloalkylalkyl; R² ishydrogen, halogen, alkyl, alkenyl, alkinyl, aralkyl, heteroarylalkyl,hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl, aryloxy,arylamino, heteroarylamino, NH₂—, monoalkylamino, dialkylamino,heterocyclyl, arylalkylamino, heteroarylalkylamino, aryl, arylalkoxy, orheteroarylalkoxy; R³ is hydrogen, alkyl, NH₂—, monoalkylamino,dialkylamino, or alkoxy; R⁴ is hydrogen, alkyl, cycloalkyl, alkoxy,hydroxy, NH₂—, monoalkylamino, dialkylamino, acetylamino, cyano,hydroxyalkyl, alkoxyalkyl, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy,heterocyclyl, heterocyclyloxy, heterocyclyloxyalkoxy, hydroxyalkoxy,alkoxycarbonyl, carboxy, heterocyclylalkyl, alkyl-SO₂—, or aryl-SO₂—; R⁵is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, NH₂—, monoalkylamino,dialkylamino, acetylamino, cyano, hydroxyalkyl, alkoxyalkyl,cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclyl,heterocyclyloxy, heterocyclyloxyalkoxy, hydroxyalkoxy, alkoxycarbonyl,carboxy, heterocyclylalkyl, alkyl-SO₂—, or aryl-SO₂—; A is a 5- to10-membered mono- or bicyclic saturated heterocyclic ring comprising thenitrogen atom which is attached to the quinoline ring or a 5- to10-membered mono- or bicyclic saturated heterocyclic ring comprising thenitrogen atom which is attached to the quinoline ring, which issubstituted by one or two further heteroatoms which are independentlyselected from the group consisting or oxygen, sulfur and nitrogen; or apharmaceutically acceptable salt or ester thereof.
 2. The compoundaccording to claim 1, wherein R¹ is hydrogen, alkyl, alkoxyalkyl,alkenyl, alkinyl, hydroxyalkyl, aralkyl, heterocyclylalkyl,cycloalkylalkyl, NH₂—SO₂—, monoalkylamino-SO₂—, dialkylamino-SO₂—, oralkyl-SO₂—; R⁴ is hydrogen, alkyl, alkoxy, hydroxy, NH₂—,monoalkylamino, dialkylamino, acetylamino, or cyano; R⁵ is hydrogen; andA is a saturated ring consisting of the nitrogen atom which is attachedto the quinoline ring and a —(CH₂)_(n)— moiety with n being 4, 5, or 6.3. The compound according to claim 1, wherein R¹ is hydrogen,cycloalkylalkyl, aralkyl, or heteroarylalkyl.
 4. The compound accordingto claim 3, wherein R¹ is hydrogen, aralkyl or heteroarylalkyl.
 5. Thecompound according to claim 4, wherein R¹ is hydrogen, phenylalkyl,pyridinylalkyl, phenylalkyl wherein the phenyl cycle is substituted byone to three substituents independently selected from the groupconsisting of alkoxy, cyano and halogen, and pyridinylalkyl wherein thepyridinyl cycle is substituted by one to three substituentsindependently selected from the group consisting of alkoxy, cyano andhalogen.
 6. The compound according to claim 5, wherein R¹ is hydrogen,cyclopropylmethyl, (methoxyphenyl) methyl, (cyanophenyl) methyl,(chlorophenyl) methyl, pyridinylmethyl, chloropyridinylmethyl, orfluoropyridinylmethyl.
 7. The compound according to claim 1, wherein R²is hydrogen, alkyl or halogen.
 8. The compound according to claim 7,wherein R² is hydrogen.
 9. The compound according to claim 7, wherein R²is alkyl.
 10. The compounds according to claim 7, wherein R² ishydrogen, butyl, fluoro, chloro or bromo.
 11. The compound according toclaim 1, wherein R³ is hydrogen, alkyl, or NH₂—.
 12. The compoundaccording to claim 11, wherein R³ is alkyl.
 13. The compound accordingto claim 12, wherein R³ is methyl.
 14. The compound according to claim1, wherein R⁴ is hydrogen, alkoxy, alkoxyalkyl, hydroxyalkyl or hydroxy.15. The compound according to claim 14, wherein R⁴ is hydrogen.
 16. Thecompound according to claim 1, wherein A is a pyrrolidinyl or azepanylring.
 17. The compound according to claim 16, wherein A is apyrrolidinyl ring.
 18. The compound according to claim 1, wherein R⁵ ishydrogen.
 19. A compound of formula:

wherein: R^(1′) is hydrogen, phenylalkyl, pyridinylalkyl, phenylalkylwherein the phenyl cycle is substituted by a substituent selected fromthe group consisting of alkoxy, cyano and halogen, and pyridinylalkylwherein the pyridinyl cycle is substituted by a substituent selectedfrom the group consisting of alkoxy, cyano and halogen; R^(2′) is ishydrogen, alkyl or halogen; R^(3′) is hydrogen or alkyl; A′ is selectedfrom the group consisting of pyrrolidinyl, pyrrolidinyl substituted byhydroxy, alkyloxy, hydroxyalkyl or alkyloxyalkyl, and azepanyl; or apharmaceutically acceptable salt or ester thereof.
 20. The compoundaccording to claim 19, wherein R^(3′) is hydrogen or methyl.
 21. Thecompound according to claim 20, wherein R^(3′) is hydrogen.
 22. Thecompound according to claim 21, wherein A′ is pyrrolidinyl.
 23. Thecompound according to claim 22, wherein R^(2′) is alkyl.
 24. Thecompound according to claim 23, wherein R^(2′) is butyl.
 25. Thecompound according to claim 24, wherein R^(1′) is hydrogen.
 26. Thecompound according to claim 25 which is6-butyl-4-pyrrolidin-1-yl-quinolin-7-ol or a pharmaceutically acceptablesalt or ester thereof.
 27. The compound according to claim 24, whereinR^(1′) is (cyanophenyl)methyl.
 28. The compound according to claim 27which is4-(6-butyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile or apharmaceutically acceptable salt or ester thereof.
 29. The compoundaccording to claim 20, wherein R^(3′) is methyl.
 30. The compoundaccording to claim 29, wherein A′ is azepanyl.
 31. The compoundaccording to claim 30, wherein R² is hydrogen.
 32. The compoundaccording to claim 31, wherein R^(1′) is pyridinylmethyl.
 33. Thecompound according to claim 32 which is4-azepan-1-yl-2-methyl-7-(pyridin-4-ylmethoxy)-quinoline or apharmaceutically acceptable salt or ester thereof.
 34. The compoundaccording to claim 31, wherein R^(1′) is (cyanophenyl)methyl.
 35. Thecompound according to claim 34 which is4-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile or apharmaceutically acceptable salt or ester thereof.
 36. The compoundaccording to claim 34 which is3-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile or apharmaceutically acceptable salt or ester thereof.
 37. The compoundaccording to claim 29, wherein A′ is pyrrolidinyl or pyrrolidinyl whichis substituted by hydroxy, alkyloxy, hydroxyalkyl or alkyloxyalkyl. 38.The compound according to claim 37, wherein A′ is pyrrolidinyl.
 39. Thecompound according to claim 38, wherein R^(2′) is hydrogen or halogen.40. The compound according to claim 39, wherein R^(2′) is hydrogen. 41.The compound according to claim 40, wherein R^(1′) is hydrogen,phenylalkyl wherein the phenyl cycle is substituted by a substituentselected from the group consisting of alkoxy, cyano and halogen, andpyridinylalkyl wherein the pyridinyl cycle is substituted by asubstituent selected from the group consisting of alkoxy, cyano andhalogen.
 42. The compound according to claim 41, wherein R^(1′) ishydrogen.
 43. The compound according to claim 42 which is2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol or a pharmaceuticallyacceptable salt or ester thereof.
 44. The compound according to claim41, wherein R^(1′) is (methoxyphenyl)methyl.
 45. The compound accordingto claim 44 which is7-(3-methoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline or apharmaceutically acceptable salt or ester thereof.
 46. The compoundaccording to claim 41, wherein R^(1′) is (cyanophenyl)methyl.
 47. Thecompound according to claim 46 which is2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile or apharmaceutically acceptable salt or ester thereof.
 48. The compoundaccording to claim 46 which is4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile or apharmaceutically acceptable salt or ester thereof.
 49. The compoundaccording to claim 41, wherein R^(1′) is (chlorophenyl)methyl.
 50. Thecompound according to claim 49 which is7-(3-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline or apharmaceutically acceptable salt or ester thereof.
 51. The compoundaccording to claim 49 which is7-(4-chloro-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline or apharmaceutically acceptable salt or ester thereof.
 52. The compoundaccording to claim 41, wherein R^(1′) is (chloropyridinyl)methyl. 53.The compound according to claim 52 which is7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline ora pharmaceutically acceptable salt or ester thereof.
 54. The compoundaccording to claim 39, wherein R^(2′) is halogen.
 55. The compoundaccording to claim 54, wherein R^(2′) is fluoro.
 56. The compoundaccording to claim 55, wherein R^(1′) is (cyanophenyl)methyl.
 57. Thecompound according to claim 56 which is4-(6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrileor a pharmaceutically acceptable salt or ester thereof.
 58. The compoundaccording to claim 57, wherein R^(1′) is (fluoropyridinyl)methyl. 59.The compound according to claim 58 which is6-fluoro-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinolineor a pharmaceutically acceptable salt or ester thereof.
 60. The compoundaccording to claim 57, wherein R^(1′) is (chloropyridinyl)methyl. 61.The compound according to claim 60 which is7-(2-chloro-pyridin-3-ylmethoxy)-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolineor a pharmaceutically acceptable salt or ester thereof.
 62. The compoundaccording to claim 37, wherein A′ is pyrrolidinyl which is substitutedby hydroxy, alkyloxy, hydroxyalkyl or alkyloxyalkyl.
 63. The compoundaccording to claim 62, wherein A′ is pyrrolidinyl which is substitutedby hydroxy.
 64. The compound according to claim 63, wherein R^(1′) is(cyanophenyl)methyl.
 65. The compound according to claim 64, whereinR^(2′) is hydrogen.
 66. The compound according to claim 65 which is(S)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileor a pharmaceutically acceptable salt or ester thereof.
 67. The compoundaccording to claim 65 which is(R)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileor a pharmaceutically acceptable salt or ester thereof.
 68. The compoundaccording to claim 62, wherein A′ is pyrrolidinyl which is substitutedby alkyloxy.
 69. The compound according to claim 68, wherein A′ ispyrrolidinyl which is substituted by methoxy.
 70. The compound accordingto claim 69, wherein R^(1′) is (cyanophenyl)methyl.
 71. The compoundaccording to claim 70 which is(S)-4-[4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileor a pharmaceutically acceptable salt or ester thereof.
 72. The compoundaccording to claim 68, wherein A′ is pyrrolidinyl which is substitutedby ethoxy.
 73. The compound according to claim 72, wherein R^(2′) ishydrogen.
 74. The compound according to claim 73, wherein R^(1′) is(cyanophenyl)methyl.
 75. The compound according to claim 74 which is(S)-4-[4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileor a pharmaceutically acceptable salt or ester thereof.
 76. The compoundaccording to claim 73, wherein R^(1′) is (fluoropyridinyl)methyl. 77.The compound according to claim 76 which is (S)4-(3-ethoxy-pyrrolidin-1-yl)-7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-quinolineor a pharmaceutically acceptable salt or ester thereof.
 78. The compoundaccording to claim 73, wherein R^(1′) is (chloropyridinyl)methyl. 79.The compound according to claim 78 which is (S)7-(2-chloro-pyridin-3-ylmethoxy)-4-(3-ethoxy-pyrrolidin-1-yl)-2-methyl-quinolineor a pharmaceutically acceptable salt or ester thereof.
 80. The compoundaccording to claim 62, wherein A′ is pyrrolidinyl which is substitutedby hydroxyalkyl.
 81. The compound according to claim 80, wherein A′ ispyrrolidinyl which is substituted by hydroxymethyl.
 82. The compoundaccording to claim 81, wherein R^(2′) is hydrogen.
 83. The compoundaccording to claim 82, wherein R^(1′) is (fluoropyridinyl)methyl. 84.The compound according to claim 83 which is(S)-{1-[7-(2-fluoro-pyridin-3-ylmethoxy)-2-methyl-quinolin-4-yl]-pyrrolidin-2-yl}-methanolor a pharmaceutically acceptable salt or ester thereof.
 85. The compoundaccording to claim 82, wherein R^(1′) is (chloropyridinyl)methyl. 86.The compound according to claim 85 which is(S)-{1-[7-(2-chloro-pyridin-3-ylmethoxy)-2-methyl-quinolin-4-yl]-pyrrolidin-2-yl}-methanolor a pharmaceutically acceptable salt or ester thereof.
 87. The compoundaccording to claim 82, wherein R^(1′) is (cyanophenyl)methyl.
 88. Thecompound according to claim 87 which is(S)-4-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileor a pharmaceutically acceptable salt or ester thereof.
 89. The compoundaccording to claim 87 which is(R)-4-[4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileor a pharmaceutically acceptable salt or ester thereof.
 90. The compoundaccording to claim 81, wherein R^(2′) is halogen.
 91. The compoundaccording to claim 90, wherein R^(2′) is fluoro.
 92. The compoundaccording to claim 91, wherein R^(1′) is (cyanophenyl)methyl.
 93. Thecompound according to claim 92 which is(S)-4-[6-fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrileor a pharmaceutically acceptable salt or ester thereof.
 94. The compoundaccording to claim 62, wherein A′ is pyrrolidinyl which is substitutedby alkyloxyalkyl.
 95. The compound according to claim 94, wherein A′ ispyrrolidinyl which is substituted by methoxymethyl.
 96. The compoundaccording to claim 95, wherein R^(2′) is hydrogen.
 97. The compoundaccording to claim 96, wherein R^(1′) is (fluoropyridinyl)methyl. 98.The compound according to claim 97 which is(S)-7-(2-fluoro-pyridin-3-ylmethoxy)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolineor a pharmaceutically acceptable salt or ester thereof.
 99. The compoundaccording to claim 96, wherein R^(1′) is (chloropyridinyl)methyl. 100.The compound according to claim 99 which is(S)-7-(2-chloro-pyridin-3-ylmethoxy)-4-(2-methoxymethyl-pyrrolidin-1-yl)-2-methyl-quinolineor a pharmaceutically acceptable salt or ester thereof.